Thienopyrrole compounds

ABSTRACT

The present disclosure relates generally to certain compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions provided herein may be used for the treatment or prevention of an autoimmune disease and/or inflammatory condition, including systemic lupus erythematosus and cutaneous lupus erythematosus.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.63/242,969, filed on Sep. 10, 2021, which is incorporated herein in itsentirety for all purposes.

FIELD

This disclosure relates generally to novel thienopyrrole compounds,pharmaceutical compositions comprising said compounds, and methods ofmaking and using said compounds and pharmaceutical compositions. In someembodiments, the novel thienopyrrole compounds provided herein may beused in the treatment of certain diseases and disorders, including, butnot limited to, an inflammatory condition, systemic lupus erythematosus,cutaneous lupus erythematosus, or lupus nephritis.

BACKGROUND

Toll-like receptors (TLRs) are a family of transmembrane immunereceptors that sense pathogens, trigger innate immune responses andprime adaptive immunity. TLR7/8/9 are endosomally localized TLRs thatrespond to single-stranded RNAs (TLR7/8) or unmethylated DNA containingcytosine-phosphate-guanine (CpG) motifs (TLR9). Activation of TLR7/8/9leads to inflammatory responses including the production of Type Iinterferons and proinflammatory cytokines, activation of B cells andantibody production, and neutrophil NETosis. Aberrant activation ofTLR7/8/9 contributes to elevated Type I interferon response, increasedpro-inflammatory cytokines, and sustained autoantibody production thatmay fuel the chronic progression of a variety of autoimmune disease andinflammatory conditions leading to broad inflammation and tissue damage.(Kawai et al., 2010, Nat Immunol 11, 373; Joosten et al., 2016, Nat RevRheomatol 12, 344; Crow et al., 2019, Lupus Sci Med 6, e000336;Garcia-Romo et al., 2011, Sci Transl Med 3, 73ra20; Kono et al., 2009,PNAS 106, 12061; Koh et al., 2013, J Immunol 190, 4982). Therefore,there is a need for compounds that are potent TLR7, and/or TLR8, and/orTLR9 antagonists that are stable and exhibit effective pharmacokineticand/or pharmacodynamic profiles.

SUMMARY

In one embodiment, provided herein is a compound of Formula I,

or a pharmaceutically acceptable salt thereof,wherein

-   -   R¹ is 8-15 membered fused tricyclic heterocyclyl or 8-15        membered fused tricyclic heteroaryl, wherein the 8-15 membered        fused tricyclic heterocyclyl and 8-15 membered fused tricyclic        heteroaryl are each independently optionally substituted with        1-4 R^(a) groups;    -   R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted with 1-4 groups independently selected from halogen        and C₁₋₆ alkoxy,        -   wherein the C₁₋₆ alkoxy is optionally substituted with 1-3            halogen groups;    -   R³ is H, halogen, —CN, C₁₋₆ alkyl, and C₃₋₇ monocyclic        cycloalkyl,        -   wherein the C₁₋₆ alkyl, and C₃₋₇ monocyclic cycloalkyl, are            each independently optionally substituted with 1-3 groups            independently selected from —OH, halogen, —CN, and C₁₋₄            alkoxy,            -   wherein the C₁₋₄ alkoxy is optionally substituted with                1-3 halogen groups;    -   Z is C₁₋₆ alkyl, —C(O)R¹³—C(O)NR⁶R⁷, C₃₋₇ monocyclic cycloalkyl,        C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic        cycloalkyl, 4-7 membered monocyclic heterocyclyl, phenyl, 5-6        membered monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4            R^(b) groups;        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered            monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-2 R⁸ groups and are each independently optionally            substituted with 1-3 R^(a) groups;    -   R⁶ is C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered        monocyclic heterocyclyl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, or        7-10 membered spirocyclic heterocyclyl,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered            monocyclic heterocyclyl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            and 7-10 membered spirocyclic heterocyclyl are each            independently optionally substituted with 1-4 R^(a) groups;    -   R¹³ is 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   R⁷ is H, C₁₋₆ alkyl, C₃₋₇ monocyclic cycloalkyl, or 4-6 membered        monocyclic heterocyclyl, wherein the C₁₋₆ alkyl, C₃₋₇ monocyclic        cycloalkyl, and 4-6 membered monocyclic heterocyclyl are each        independently optionally substituted with 1-4 groups        independently selected from —OH, halogen, —CN, and C₁₋₆ alkoxy;    -   each R⁸ independently is halogen, —C(O)R⁹, —NR¹⁰R¹⁰, C₁₋₆ alkyl,        C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,        C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered monocyclic        heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-10        membered fused bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR⁵, —C(O)N(R⁵)(R⁵),        —N(R⁵)₂(R⁵)⁺, —N(R⁵)C(O)R⁵, —N(R⁵)C(O)OR⁵, —N(R⁵)C(O)N(R⁵)(R⁵),        —N(R⁵)S(O)₂(R^(5a)), —NR⁵S(O)₂N(R⁵)(R⁵), —NR⁵S(O)₂O(R^(5a)),        —OC(O)N(R⁵)(R⁵), —S(O)R^(5a), —S(O)(NH)R⁵, —S(O)₂R^(5a),        —S(O)₂N(R⁵)(R⁵), or —N═S(R^(5a))(R^(5a))═O,        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4            R^(b) groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered            monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-4 R^(a) groups;    -   each R⁹ independently is C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused        bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   each R⁵ and R¹⁰ independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are            each independently optionally substituted with 1-4 R^(b)            groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   each R^(5a) independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are            each independently optionally substituted with 1-4 R^(b)            groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   each R^(a) independently is oxo, imino, halogen, —NO₂, —N₃, —CN,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic        cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridged        bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7 membered        monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,        8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹, —N(R¹¹)₂(R¹¹)⁺,        —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹),        —N(R¹¹)S(O)₂(R^(11a)), —NR¹¹S(O)₂N(R¹¹)(R¹¹),        —NR¹¹S(O)₂O(R^(11a)), —OC(O)R¹¹, —OC(O)OR¹¹, —OC(O)N(R¹¹)(R¹¹),        —SR¹¹, —S(O)R^(11a), —S(O)(NH)R¹¹, —S(O)₂R^(11a),        —S(O)₂N(R¹¹)(R¹¹) or —N═S(R^(11a))(R^(11a))═O,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are            each independently optionally substituted with 1-3 R^(c)            groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-3 R^(d) groups,    -   each R^(b) independently is oxo, imino, halogen, —NO₂, —N₃, —CN,        C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,        C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7        membered monocyclic heterocyclyl, 5-6 membered monocyclic        heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 8-10        membered bridged bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹, —N(R¹¹)₂(R¹¹)⁺,        —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹),        —N(R¹¹)S(O)₂(R^(11a)), —NR¹¹S(O)₂N(R¹¹)(R¹¹),        —NR¹¹S(O)₂O(R^(11a)), —OC(O)R¹¹, —OC(O)OR¹¹, —OC(O)N(R¹¹)(R¹¹),        —SR¹¹, —S(O)R^(11a), —S(O)(NH)R¹¹, —S(O)₂R^(11a),        —S(O)₂N(R¹¹)(R¹¹), or —N═S(R^(11a))(R^(11a))═O,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-3 R^(d) groups;    -   each R^(c) independently is halogen, —CN, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, 7-10 membered spirocyclic        heterocyclyl, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)(R¹²),        —NR¹²R¹², —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R^(12a)),        —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a),        —S(O)(NH)R¹², —S(O)₂R^(12a), —S(O)₂N(R¹²)(R¹²) or        —N═S(R^(12a))(R^(12a))═O;    -   each R^(d) independently is oxo, halogen, —CN, C₁₋₆ alkyl, C₇₋₁₀        fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl,        phenyl, naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6        membered monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, 7-10 membered spirocyclic        heterocyclyl, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)(R¹²),        —NR¹²R¹², —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R^(12a)),        —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a),        —S(O)(NH)R¹², —S(O)₂R^(12a), —S(O)₂N(R¹²)(R¹²) or        —N═S(R^(12a))(R^(12a))═O,        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3            groups independently selected from —OH, halogen, —CN, and            C₁₋₃ alkoxy;    -   each R¹¹ independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇            monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,            C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7            membered monocyclic heterocyclyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-3 R^(c) groups;    -   each R^(11a) independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇            monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,            C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7            membered monocyclic heterocyclyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-3 R^(c) groups;    -   each R¹² independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl;    -   each R¹², independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl;    -   wherein each 4-membered monocyclic heterocyclyl independently        has 1 ring heteroatom selected from N, O, and S;    -   wherein each 5-7 membered monocyclic heterocyclyl independently        has 1-2 ring heteroatoms independently selected from N, O, and        S;    -   wherein each 6-membered bridged bicyclic heterocyclyl        independently has 1 ring heteroatom selected from N, O, and S;    -   wherein each 7-membered bridged bicyclic heterocyclyl        independently has 1-2 ring heteroatoms independently selected        from N, O, and S;    -   wherein each 5-6 membered monocyclic heteroaryl, 8-10 membered        fused bicyclic heterocyclyl, 8-10 membered bridged bicyclic        heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10        membered spirocyclic heterocyclyl independently have 1-4 ring        heteroatoms independently selected from N, O, and S; and    -   wherein each 8-15 membered fused tricyclic heterocyclyl and 8-15        membered fused tricyclic heteroaryl independently have 1-7 ring        heteroatoms independently selected from N, O, and S.

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound provided herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient or carrier.

In one embodiment, provided herein is a method of inhibiting toll-likereceptor 7 and/or 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, provided herein is a method of inhibiting toll-likereceptor 7 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, provided herein is a method of inhibiting toll-likereceptor 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, provided herein is a method of treating a disease ordisorder associated with elevated toll-like receptor 7 and/or 8 activityin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein.

In one embodiment, provided herein is a method of treating a disease ordisorder associated with elevated toll-like receptor 7 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein.

In one embodiment, provided herein is a method of treating a disease ordisorder associated with elevated toll-like receptor 8 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein.

In one embodiment, provided herein is a method of treating aninflammatory condition in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, provided herein is a method of treating systemiclupus erythematosus in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, provided herein is a method of treating cutaneouslupus erythematosus in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, provided herein is a method of treating lupusnephritis in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in therapy.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of inhibiting toll-likereceptor 7 and/or 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of the pharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of inhibiting toll-likereceptor 7 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of the pharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of inhibiting toll-likereceptor 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of the pharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of treating a disease ordisorder associated with elevated toll-like receptor 7 and/or 8 activityin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of the compound, or a pharmaceuticallyacceptable salt thereof, or a therapeutically effective amount of thepharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of treating a disease ordisorder associated with elevated toll-like receptor 7 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of the compound, or a pharmaceuticallyacceptable salt thereof, or a therapeutically effective amount of thepharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of treating a disease ordisorder associated with elevated toll-like receptor 8 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of the compound, or a pharmaceuticallyacceptable salt thereof, or a therapeutically effective amount of thepharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of treating aninflammatory condition in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of the pharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of treating systemiclupus erythematosus in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of the pharmaceutical composition.

In one embodiment, provided herein is a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein for use in a method of treating cutaneouslupus erythematosus in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound, or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of the pharmaceutical compositiontherapeutically effective amount of the pharmaceutical composition.

DETAILED DESCRIPTION I. Definitions

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. It must be noted that as used herein and in the appendedclaims, the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “the compound” includes a plurality of such compounds andreference to “the assay” includes reference to one or more assays andequivalents thereof known to those skilled in the art, and so forth.

As used in the present disclosure, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named. A solid line comingout of the center of a ring (including a fused, bridged or spirocyclicring system) indicates that the point of attachment for a substituent onthe ring can be at any ring atom. For example, R^(aa) in the belowstructure can be attached to any of the five carbon ring atoms or R^(aa)can replace the hydrogen attached to the nitrogen ring atom:

As another example, R^(aa) in the below structure:

R^(aa) can be attached to any of the numbered positions shown below:

A solid line coming out of the center of a ring (including a fused,bridged, or spirocyclic ring system) indicates that the point ofattachment for the ring system to the rest of the compound can be at anyring atom of the fused, bridged, or spirocyclic ring system. Forexample, in the below structure:

the monocyclic heterocyclyl can be attached to the rest of the compoundat any of the numbered positions shown below:

As another example, in the below fused bicyclic heterocyclic structure,

the fused bicyclic heterocyclyl can be attached to the rest of thecompound at any of the eight numbered positions shown below:

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms. Likewise, the term “x-y membered” rings,wherein x and y are numerical ranges, such as “3 to 12-memberedheterocyclyl”, refers to a ring containing x-y atoms (i.e., 3-12), ofwhich up to 80% may be heteroatoms, such as N, O, S, P, and theremaining atoms are carbon.

Also, certain commonly used alternative chemical names may or may not beused. For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, or alkylyl group, an “arylene” group oran “arylenyl” group, or arylyl group, respectively.

“A compound disclosed herein” or “a compound of the present disclosure”or “a compound provided herein” or “a compound described herein” refersto the compounds of Formula I. Also included are the specific compoundsof Examples 1 to 68.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, the term “about X” includesdescription of “X”.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to12 carbon atoms (i.e., C₁₋₁₂ alkyl), 1 to 8 carbon atoms (i.e., C₁₋₈alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl), 1 to 4 carbon atoms(i.e., C₁₋₄ alkyl), 1 to 3 carbon atoms (i.e., C₁₋₃ alkyl), or 1 to 2carbon atoms (i.e., C₁₋₂ alkyl). Examples of alkyl groups includemethyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, and 3-methylpentyl. When an alkyl residue having a specificnumber of carbons is named by chemical name or identified by molecularformula, all positional isomers having that number of carbons may beencompassed; thus, for example, “butyl” includes n-butyl (i.e.—(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e.—CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includesn-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkylene” refers to a divalent and unbranched saturated hydrocarbonchain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C₁₋₂₀alkylene), 1 to 12 carbon atoms (i.e., C₁₋₁₂ alkylene), 1 to 8 carbonatoms (i.e., C₁₋₈ alkylene), 1 to 6 carbon atoms (i.e., C₁₋₆ alkylene),1 to 4 carbon atoms (i.e., C₁₋₄ alkylene), 1 to 3 carbon atoms (i.e.,C₁₋₃ alkylene), or 1 to 2 carbon atoms (i.e., C₁₋₂ alkylene). Examplesof alkylene groups include methylene, ethylene, propylene, butylene,pentylene, and hexylene. In some embodiments, an alkylene is optionallysubstituted with an alkyl group. Examples of substituted alkylene groupsinclude —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —CH₂CH(CH₂CH₃)—, —CH₂C(CH₃)₂—,—C(CH₃)₂CH₂—, —CH(CH₃)CH(CH₃)—, —CH₂C(CH₂CH₃)(CH₃)—, and —CH₂C(CH₂CH₃)₂.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Haloalkoxy”refers to an alkoxy group as defined above, wherein one or more hydrogenatoms are replaced by a halogen.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(═O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(═O)R^(z), wherein R^(y) and R^(z) are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, haloalkyl,heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionallysubstituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of whichmay be optionally substituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Cycloalkoxy” refers to the group “cycloalkyl-O—”. Examples ofcycloalkoxy groups include but are not limited to:

“Bridged” refers to a ring fusion wherein different atoms on a ring arejoined by a divalent substituent, such as an alkylenyl group, analkylenyl group containing one or two heteroatoms, or a singleheteroatom. Quinuclidinyl and adamantanyl are examples of bridged ringsystems.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkylene” refers to a divalent and unbranched saturatedhydrocarbon chain having one, two, or three heteroatoms selected fromNH, O, or S. As used herein, a heteroalkylene has 1 to 20 carbon atomsand one, two, or three heteroatoms selected from NH, O, and S (i.e.,C₁₋₂₀ heteroalkylene); 1 to 8 carbon atoms and one, two, or threeheteroatoms selected from NH, O, and S (i.e., C₁₋₈ heteroalkylene); 1 to6 carbon atoms and one, two, or three heteroatoms selected from NH, O,and S S (i.e., C₁₋₆ heteroalkylene); 1 to 4 carbon atoms and one, two,or three heteroatoms selected from NH, O, and S (i.e., C₁₋₄heteroalkylene); 1 to 3 carbon atoms and one, two, or three heteroatomsselected from NH, O, and S (i.e., C₁₋₃ heteroalkylene); or 1 to 2 carbonatoms and one, two, or three heteroatoms selected from NH, O, and S(i.e., C₁₋₃ heteroalkylene). For example, —CH₂O— is a C₁ heteroalkyleneand —CH₂SCH₂— is a C₂ heteroalkylene. Examples of heteroalkylene groupsinclude —CH₂CH₂OCH₂—, —CH₂SCH₂OCH₂—, —CH₂O—, and —CH₂NHCH₂—. In someembodiments, a heteroalkylene is optionally substituted with an alkylgroup. Examples of substituted heteroalkylene groups include—CH(CH₃)N(CH₃)CH₂—, —CH₂OCH(CH₃)—, —CH₂CH(CH₂CH₃)S—, —CH₂NHC(CH₃)₂—,—C(CH₃)₂SCH₂—, —CH(CH₃)N(CH₃)CH(CH₃)O—, —CH₂SC(CH₂CH₃)(CH₃)—, and—CH₂C(CH₂CH₃)₂NH—.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 carbon ring atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 ringheteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, oxygen, and sulfur. Examples of heteroaryl groups includepyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to anon-aromatic cyclic alkyl group, with one or more ring heteroatomsindependently selected from nitrogen, oxygen and sulfur. As used herein,“heterocyclyl” or “heterocyclic ring” or “heterocycle” refer to ringsthat are saturated or partially saturated unless otherwise indicated,e.g., in some embodiments “heterocyclyl” or “heterocyclic ring” or“heterocycle” refers to rings that are partially saturated wherespecified. The term “heterocyclyl” or “heterocyclic ring” or“heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclylgroup having at least one double bond). A heterocyclyl may be a singlering or multiple rings wherein the multiple rings may be fused, bridged,or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 carbon ring atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 carbon ring atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 carbon ring atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 carbon ringatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 carbon ring atoms (i.e., C₃₋₈heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. Examples of heterocyclylgroups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl,dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term“bridged-heterocyclyl” refers to a four- to ten-membered cyclic moietyconnected at two non-adjacent atoms of the heterocyclyl with one or more(e.g., 1 or 2) four- to ten-membered cyclic moiety having at least oneheteroatom where each heteroatom is independently selected fromnitrogen, oxygen, and sulfur. As used herein, “bridged-heterocyclyl”includes bicyclic and tricyclic ring systems. Also as used herein, theterm “spiro-heterocyclyl” refers to a ring system in which a three- toten-membered heterocyclyl has one or more additional ring, wherein theone or more additional ring is three- to ten-membered cycloalkyl orthree- to ten-membered heterocyclyl, where a single atom of the one ormore additional ring is also an atom of the three- to ten-memberedheterocyclyl. Examples of the spiro-heterocyclyl include bicyclic andtricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. As usedherein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring”are used interchangeably. In some embodiments, a heterocyclyl issubstituted with an oxo group.

“Heterocycloxy” refers to the group “—O(heterocyclyl)”. Examples ofheterocycloxy groups include but are not limited to —O(pyrrolidinyl),—O(tetrahydrofuranyl), —O(piperidinyl), —O(morpholinyl), —O(oxetanyl),and —O(2-oxa-7-azaspiro[3.5]nonanyl).

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R^(bb), where R^(bb) is alkyl,haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples ofsulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, andtoluenesulfonyl.

Whenever the graphical representation of a group terminates in a singlybonded nitrogen atom, that group represents an —NH group unlessotherwise indicated. Similarly, unless otherwise expressed, hydrogenatom(s) are implied and deemed present where necessary in view of theknowledge of one of skill in the art to complete valency or providestability.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” means that any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino,imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl,thiocyanate, thiol, thione, or combinations thereof. Polymers or similarindefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g., a substituted aryl having asubstituted alkyl which is itself substituted with a substituted arylgroup, which is further substituted by a substituted heteroalkyl group,etc.) are not intended for inclusion herein. Unless otherwise noted, themaximum number of serial substitutions in compounds described herein isthree. For example, serial substitutions of substituted aryl groups withtwo other substituted aryl groups are limited to ((substitutedaryl)substituted aryl) substituted aryl. Similarly, the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with 5 fluorines or heteroaryl groupshaving two adjacent oxygen ring atoms). Such impermissible substitutionpatterns are well known to the skilled artisan. When used to modify achemical group, the term “substituted” may describe other chemicalgroups defined herein. For example, the term “substituted aryl”includes, but is not limited to, “alkylaryl.” Unless specifiedotherwise, where a group is described as optionally substituted, anysubstituents of the group are themselves unsubstituted.

In some embodiments, a substituted cycloalkyl, a substitutedheterocyclyl, a substituted aryl, and/or a substituted heteroarylincludes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl thathas a substituent on the ring atom to which the cycloalkyl,heterocyclyl, aryl, and/or heteroaryl is attached to the rest of thecompound. For example, in the below moiety, the cyclopropyl issubstituted with a methyl group:

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Wherecompounds are represented in their chiral form, it is understood thatthe embodiment encompasses, but is not limited to, the specificdiastereomerically or enantiomerically enriched form. Where chirality isnot specified but is present, it is understood that the embodiment isdirected to either the specific diastereomerically or enantiomericallyenriched form; or a racemic or scalemic mixture of such compound(s). Asused herein, “scalemic mixture” is a mixture of stereoisomers at a ratioother than 1:1.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 isa “scalemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any compounds provided herein.

Some of the compounds provided herein exist as tautomeric isomers.Tautomeric isomers are in equilibrium with one another. For example,amide containing compounds may exist in equilibrium with imidic acidtautomers. Regardless of which tautomer is shown, and regardless of thenature of the equilibrium among tautomers, the compounds are understoodby one of ordinary skill in the art to comprise both amide and imidicacid tautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds provided herein are also provided.Hydrates of the compounds provided herein are also provided.

Any formula or structure provided herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ²H, ³H, ¹³C and ¹⁴C are incorporated,are also provided herein. Such isotopically labelled compounds may beuseful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays or in radioactive treatment ofpatients.

The present disclosure also includes compounds of Formula I, in whichfrom 1 to n hydrogens attached to a carbon atom is/are replaced bydeuterium, in which n is the number of hydrogens in the molecule. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half-life of any compound of Formula I whenadministered to a mammal, particularly a human. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,”Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of the presentdisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to absorption, distribution, metabolism andexcretion (ADME). Substitution with heavier isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life, reduceddosage requirements and/or an improvement in therapeutic index. An ¹⁸Flabeled compound may be useful for PET or SPECT studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure, any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosure,any atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono,di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines,and the like. Specific examples of suitable amines include, by way ofexample only, isopropylamine, trimethyl amine, diethyl amine,tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,2-dimethylaminoethanol, piperazine, piperidine, morpholine,N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (i.e., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(i.e., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (i.e., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (i.e., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival).

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient toimprove a symptom of a disease or condition responsive to inhibition oftoll-like receptor 7, 8, and/or 9. The therapeutically effective amountmay vary depending on the subject, and the disease or condition beingtreated, the weight and age of the subject, the severity of the diseaseor condition, and the manner of administering, which can readily bedetermined by one of ordinary skill in the art.

II. Compounds

In one embodiment, provided herein is a compound of Formula I,

or a pharmaceutically acceptable salt thereof,wherein

-   -   R¹ is 8-15 membered fused tricyclic heterocyclyl or 8-15        membered fused tricyclic heteroaryl, wherein the 8-15 membered        fused tricyclic heterocyclyl and 8-15 membered fused tricyclic        heteroaryl are each independently optionally substituted with        1-4 R^(a) groups;    -   R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted with 1-4 groups independently selected from halogen        and C₁₋₆ alkoxy, wherein the C₁₋₆ alkoxy is optionally        substituted with 1-3 halogen groups;    -   R³ is H, halogen, —CN, C₁₋₆ alkyl, and C₃₋₇ monocyclic        cycloalkyl,        -   wherein the C₁₋₆ alkyl and C₃₋₇ monocyclic cycloalkyl are            each independently optionally substituted with 1-3 groups            independently selected from —OH, halogen, —CN, and C₁₋₄            alkoxy,            -   wherein the C₁₋₄ alkoxy is optionally substituted with                1-3 halogen groups;    -   Z is C₁₋₆ alkyl, —C(O)R¹³—C(O)NR⁶R⁷, C₃₋₇ monocyclic cycloalkyl,        C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic        cycloalkyl, 4-7 membered monocyclic heterocyclyl, phenyl, 5-6        membered monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4            R^(b) groups;        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered            monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-2 R⁸ groups and are each independently optionally            substituted with 1-3 R^(a) groups;    -   R⁶ is C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered        monocyclic heterocyclyl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, or        7-10 membered spirocyclic heterocyclyl,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered            monocyclic heterocyclyl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            and 7-10 membered spirocyclic heterocyclyl are each            independently optionally substituted with 1-4 R^(a) groups;    -   R¹³ is 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   R⁷ is H, C₁₋₆ alkyl, C₃₋₇ monocyclic cycloalkyl, or 4-6 membered        monocyclic heterocyclyl, wherein the C₁₋₆ alkyl, C₃₋₇ monocyclic        cycloalkyl, and 4-6 membered monocyclic heterocyclyl are each        independently optionally substituted with 1-4 groups        independently selected from —OH, halogen, —CN, and C₁₋₆ alkoxy;    -   each R⁸ independently is halogen, —C(O)R⁹, —NR¹⁰R¹⁰, C₁₋₆ alkyl,        C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,        C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered monocyclic        heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-10        membered fused bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR⁵, —C(O)N(R⁵)(R⁵),        —N(R⁵)₂(R⁵)⁺, —N(R⁵)C(O)R⁵, —N(R⁵)C(O)OR⁵, —N(R⁵)C(O)N(R⁵)(R⁵),        —N(R⁵)S(O)₂(R^(5a)), —NR⁵S(O)₂N(R⁵)(R⁵), —NR⁵S(O)₂O(R^(5a)),        —OC(O)N(R⁵)(R⁵), —S(O)R^(5a), —S(O)(NH)R⁵, —S(O)₂R^(5a),        —S(O)₂N(R⁵)(R⁵), or —N═S(R^(5a))(R^(5a))═O,        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4            R^(b) groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered            monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-4 R^(a) groups;    -   each R⁹ independently is C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused        bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   each R⁵ and R¹⁰ independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are            each independently optionally substituted with 1-4 R^(b)            groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   each R^(5a) independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are            each independently optionally substituted with 1-4 R^(b)            groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   each R^(a) independently is oxo, imino, halogen, —NO₂, —N₃, —CN,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic        cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridged        bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7 membered        monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,        8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹, —N(R¹¹)₂(R¹¹)⁺,        —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹),        —N(R¹¹)S(O)₂(R^(11a)), —NR¹¹S(O)₂N(R¹¹)(R¹¹),        —NR¹¹S(O)₂O(R^(11a)), —OC(O)R¹¹, —OC(O)OR¹¹, —OC(O)N(R¹¹)(R¹¹),        —SR¹¹, —S(O)R^(11a), —S(O)(NH)R¹¹, —S(O)₂R^(11a),        —S(O)₂N(R¹¹)(R¹¹), or —N═S(R^(11a))(R^(11a))═O,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are            each independently optionally substituted with 1-3 R^(c)            groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-3 R^(d) groups,    -   each R^(b) independently is oxo, imino, halogen, —NO₂, —N₃, —CN,        C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,        C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7        membered monocyclic heterocyclyl, 5-6 membered monocyclic        heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 8-10        membered bridged bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹, —N(R¹¹)₂(R¹¹)⁺,        —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹),        —N(R¹¹)S(O)₂(R^(11a)), —NR¹¹S(O)₂N(R¹¹)(R¹¹),        —NR¹¹S(O)₂O(R^(11a)), —OC(O)R¹¹, —OC(O)OR¹¹, —OC(O)N(R¹¹)(R¹¹),        —SR¹¹, —S(O)R^(11a), —S(O)(NH)R¹¹, —S(O)₂R^(11a),        —S(O)₂N(R¹¹)(R¹¹), or —N═S(R^(11a))(R^(11a))═O,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-3 R^(d) groups;    -   each R^(c) independently is halogen, —CN, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, 7-10 membered spirocyclic        heterocyclyl, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)(R¹²),        —NR¹²R¹², —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R^(12a)),        —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a),        —S(O)(NH)R¹², —S(O)₂R^(12a), —S(O)₂N(R¹²)(R¹²) or        —N═S(R^(12a))(R^(12a))═O;    -   each R^(d) independently is oxo, halogen, —CN, C₁₋₆ alkyl, C₇₋₁₀        fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl,        phenyl, naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6        membered monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, 7-10 membered spirocyclic        heterocyclyl, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)(R¹²),        —NR¹²R¹²—N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R^(12a)),        —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a),        —S(O)(NH)R¹², —S(O)₂R^(12a), —S(O)₂N(R¹²)(R¹²) or        —N═S(R^(12a))(R^(12a))═O,        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3            groups independently selected from —OH, halogen, —CN, and            C₁₋₃ alkoxy;    -   each R¹¹ independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇            monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,            C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7            membered monocyclic heterocyclyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-3 R^(c) groups;    -   each R^(11a) independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇            monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,            C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7            membered monocyclic heterocyclyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-3 R^(c) groups;    -   each R¹² independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl;    -   each R¹², independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl;    -   wherein each 4-membered monocyclic heterocyclyl independently        has 1 ring heteroatom selected from N, O, and S;    -   wherein each 5-7 membered monocyclic heterocyclyl independently        has 1-2 ring heteroatoms independently selected from N, O, and        S;    -   wherein each 6-membered bridged bicyclic heterocyclyl        independently has 1 ring heteroatom selected from N, O, and S;    -   wherein each 7-membered bridged bicyclic heterocyclyl        independently has 1-2 ring heteroatoms independently selected        from N, O, and S;    -   wherein each 5-6 membered monocyclic heteroaryl, 8-10 membered        fused bicyclic heterocyclyl, 8-10 membered bridged bicyclic        heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10        membered spirocyclic heterocyclyl independently have 1-4 ring        heteroatoms independently selected from N, O, and S; and    -   wherein each 8-15 membered fused tricyclic heterocyclyl and 8-15        membered fused tricyclic heteroaryl independently have 1-7 ring        heteroatoms independently selected from N, O, and S.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₇₋₁₀ fused bicyclic cycloalkyl, 8-10membered fused bicyclic heterocyclyl, 6-10 membered bridged bicyclicheterocyclyl, or 8-10 membered fused bicyclic heteroaryl,

-   -   wherein the C₇₋₁₀ fused bicyclic cycloalkyl, 8-10 membered fused        bicyclic heterocyclyl, 6-10 membered bridged bicyclic        heterocyclyl, and 8-10 membered fused bicyclic heteroaryl are        each independently optionally substituted with 1-2 R⁸ groups and        are each independently optionally substituted with 1-3 R^(a)        groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof,

-   -   R¹ is 8-15 membered fused tricyclic heterocyclyl optionally        substituted with 1-4 R^(a) groups;    -   R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted with 1-4 groups independently selected from halogen        and C₁₋₆ alkoxy, wherein the C₁₋₆ alkoxy is optionally        substituted with 1-3 halogen groups;    -   R³ is H or C₁₋₆ alkyl,        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3            groups independently selected from —OH, halogen, —CN, and            C₁₋₄ alkoxy,            -   wherein the C₁₋₄ alkoxy is optionally substituted with                1-3 halogen groups;    -   Z is 4-7 membered monocyclic heterocyclyl, phenyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, or        7-10 membered spirocyclic heterocyclyl,        -   wherein the 4-7 membered monocyclic heterocyclyl, phenyl,            5-6 membered monocyclic heteroaryl, 8-10 membered fused            bicyclic heterocyclyl, 6-10 membered bridged bicyclic            heterocyclyl, and 7-10 membered spirocyclic heterocyclyl are            each independently optionally substituted with 1-2 R⁸ groups            and are each independently optionally substituted with 1-3            R^(a) groups;    -   each R⁸ independently is —C(O)R⁹, C₁₋₆ alkyl, 4-7 membered        monocyclic heterocyclyl, or —S(O)₂R^(5a),        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4            R^(b) groups,        -   wherein the 4-7 membered monocyclic heterocyclyl is            optionally substituted with 1-4 R^(a) groups;    -   each R⁹ independently is C₃₋₇ monocyclic cycloalkyl or 4-7        membered monocyclic heterocyclyl,        -   wherein the C₃₋₇ monocyclic cycloalkyl and 4-7 membered            monocyclic heterocyclyl are each independently optionally            substituted with 1-4 R^(a) groups;    -   R^(5a) is 4-7 membered monocyclic heterocyclyl, wherein the 4-7        membered monocyclic heterocyclyl is optionally substituted with        1-4 R^(a) groups;    -   each R^(a) independently is oxo, imino, halogen, —NO₂, —N₃, —CN,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic        cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridged        bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7 membered        monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,        8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹, —N(R¹¹)₂(R¹¹)⁺,        —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹),        —N(R¹¹)S(O)₂(R^(11a)), —NR¹¹S(O)₂N(R¹¹)(R¹¹),        —NR¹¹S(O)₂O(R^(11a)), —OC(O)R¹¹, —OC(O)OR¹¹, —OC(O)N(R¹¹)(R¹¹),        —SR¹¹, —S(O)R^(11a), —S(O)(NH)R¹¹, —S(O)₂R^(11a),        —S(O)₂N(R¹¹)(R¹¹), or —N═S(R^(11a))(R^(11a))═O,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are            each independently optionally substituted with 1-3 R^(c)            groups,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-3 R^(d) groups,    -   each R^(b) independently is oxo, imino, halogen, —NO₂, —N₃, —CN,        C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,        C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7        membered monocyclic heterocyclyl, 5-6 membered monocyclic        heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 8-10        membered bridged bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        7-10 membered spirocyclic heterocyclyl, —OR¹¹, —C(O)R¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹, —N(R¹¹)₂(R¹¹)⁺,        —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹),        —N(R¹¹)S(O)₂(R^(11a)), —NR¹¹S(O)₂N(R¹¹)(R¹¹),        —NR¹¹S(O)₂O(R^(11a)), —OC(O)R¹¹, —OC(O)OR¹¹, —OC(O)N(R¹¹)(R¹¹),        —SR¹¹, —S(O)R^(11a), —S(O)(NH)R¹¹, —S(O)₂R^(11a),        —S(O)₂N(R¹¹)(R¹¹), or —N═S(R^(11a))(R^(11a))═O,        -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic            cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,            naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6            membered monocyclic heteroaryl, 8-10 membered fused bicyclic            heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl,            8-10 membered fused bicyclic heteroaryl, and 7-10 membered            spirocyclic heterocyclyl are each independently optionally            substituted with 1-3 R^(d) groups;    -   each R^(c) independently is halogen, —CN, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, 7-10 membered spirocyclic        heterocyclyl, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)(R¹²),        —NR¹²R¹², —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R^(12a)),        —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a),        —S(O)(NH)R¹², —S(O)₂R^(12a), —S(O)₂N(R¹²)(R¹²) or        —N═S(R^(12a))(R^(12a))═O;    -   each R^(d) independently is oxo, halogen, —CN, C₁₋₆ alkyl, C₇₋₁₀        fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl,        phenyl, naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6        membered monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, 7-10 membered spirocyclic        heterocyclyl, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)(R¹²),        —NR¹²R¹², —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R^(12a)),        —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)), —OC(O)R¹²,        —OC(O)OR¹², —OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a),        —S(O)(NH)R¹², —S(O)₂R^(12a), —S(O)₂N(R¹²)(R¹²) or        —N═S(R^(12a))(R^(12a))═O;    -   each R¹¹ independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇            monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,            C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7            membered monocyclic heterocyclyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-3 R^(c) groups;    -   each R^(11a) independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl,        -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇            monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl,            C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7            membered monocyclic heterocyclyl, 5-6 membered monocyclic            heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10            membered bridged bicyclic heterocyclyl, 8-10 membered fused            bicyclic heteroaryl, and 7-10 membered spirocyclic            heterocyclyl are each independently optionally substituted            with 1-3 R^(c) groups;    -   each R¹² independently is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl;    -   each R^(12a) independently is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, or 7-10 membered spirocyclic        heterocyclyl;    -   wherein each 4-membered monocyclic heterocyclyl independently        has 1 ring heteroatom selected from N, O, and S;    -   wherein each 5-7 membered monocyclic heterocyclyl independently        has 1-2 ring heteroatoms independently selected from N, O, and        S;    -   wherein each 6-membered bridged bicyclic heterocyclyl        independently has 1 ring heteroatom selected from N, O, and S;    -   wherein each 7-membered bridged bicyclic heterocyclyl        independently has 1-2 ring heteroatoms independently selected        from N, O, and S;    -   wherein each 5-6 membered monocyclic heteroaryl, 8-10 membered        fused bicyclic heterocyclyl, 8-10 membered bridged bicyclic        heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10        membered spirocyclic heterocyclyl independently have 1-4 ring        heteroatoms independently selected from N, O, and S; and    -   wherein each 8-15 membered fused tricyclic heterocyclyl and 8-15        membered fused tricyclic heteroaryl independently have 1-7 ring        heteroatoms independently selected from N, O, and S.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof,

-   -   R¹ is 8-15 membered fused tricyclic heterocyclyl optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₆ alkyl, and C₃₋₇        monocyclic cycloalkyl;    -   R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted with 1-4 groups independently selected from halogen        and C₁₋₆ alkoxy;    -   R³ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, and C₁₋₄ alkoxy;    -   Z is 4-7 membered monocyclic heterocyclyl, phenyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, or        7-10 membered spirocyclic heterocyclyl,        -   wherein the 4-7 membered monocyclic heterocyclyl, phenyl,            5-6 membered monocyclic heteroaryl, 8-10 membered fused            bicyclic heterocyclyl, 6-10 membered bridged bicyclic            heterocyclyl, and 7-10 membered spirocyclic heterocyclyl are            each independently optionally substituted with 1-2 R⁸ groups            and are each independently optionally substituted with 1-3            groups independently selected from —OH, halogen, —CN, oxo,            —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl;    -   each R⁸ independently is —C(O)R⁹, C₁₋₆ alkyl, 4-7 membered        monocyclic heterocyclyl, or —S(O)₂R^(5a),        -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3            groups independently selected from —OH, halogen, —CN, oxo,            —NR¹¹R¹¹, —C(O)NR¹¹R¹¹, C₁₋₄ alkoxy, and R^(8a),        -   wherein the 4-7 membered monocyclic heterocyclyl is            optionally substituted with 1-3 groups independently            selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy,            and C₁₋₅ alkyl;    -   each R^(8a) independently is 4-7 membered monocyclic        heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the        4-7 membered monocyclic heterocyclyl and 5-6 membered monocyclic        heteroaryl are each independently optionally substituted with        1-3 groups independently selected from —OH, halogen, C₁₋₄        alkoxy, and C₁₋₅ alkyl;    -   each R⁹ independently is C₃₋₇ monocyclic cycloalkyl or 4-7        membered monocyclic heterocyclyl, wherein the C₃₋₇ monocyclic        cycloalkyl and 4-7 membered monocyclic heterocyclyl are each        independently optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,        C₁₋₄ alkoxy, C₁₋₅ alkyl, and 4-7 membered monocyclic        heterocyclyl;    -   R^(5a) is 4-7 membered monocyclic heterocyclyl, wherein the 4-7        membered monocyclic heterocyclyl is optionally substituted with        1-3 groups independently selected from —OH, halogen, —CN, oxo,        —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl;    -   each R¹¹ independently is H or C₁₋₆ alkyl;    -   each R¹² independently is H or C₁₋₄ alkyl;    -   wherein each 4-membered monocyclic heterocyclyl independently        has 1 ring heteroatom selected from N, O, and S;    -   wherein each 5-7 membered monocyclic heterocyclyl independently        has 1-2 ring heteroatoms independently selected from N, O, and        S;    -   wherein each 6-membered bridged bicyclic heterocyclyl        independently has 1 ring heteroatom selected from N, O, and S;    -   wherein each 7-membered bridged bicyclic heterocyclyl        independently has 1-2 ring heteroatoms independently selected        from N, O, and S;    -   wherein each 5-6 membered monocyclic heteroaryl, 8-10 membered        fused bicyclic heterocyclyl, 8-10 membered bridged bicyclic        heterocyclyl, 8-10 membered fused bicyclic heteroaryl, and 7-10        membered spirocyclic heterocyclyl independently have 1-4 ring        heteroatoms independently selected from N, O, and S; and    -   wherein each 8-15 membered fused tricyclic heterocyclyl and 8-15        membered fused tricyclic heteroaryl independently have 1-7 ring        heteroatoms independently selected from N, O, and S.

Unless specified otherwise, each 4-membered monocyclic heterocyclyl asused herein has 1 ring heteroatom selected from N, O, and S. Unlessspecified otherwise, each 5-7 membered monocyclic heterocyclyl as usedherein has 1-2 ring heteroatoms independently selected from N, O, and S.Unless specified otherwise, each 6-membered bridged bicyclicheterocyclyl as used herein has 1 ring heteroatom selected from N, O,and S. Unless specified otherwise, each 7-membered bridged bicyclicheterocyclyl as used herein has 1-2 ring heteroatoms independentlyselected from N, O, and S. Unless specified otherwise, each 5-6 memberedmonocyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 8-10membered bridged bicyclic heterocyclyl, 8-10 membered fused bicyclicheteroaryl, and 7-10 membered spirocyclic heterocyclyl as used hereinindependently have 1-4 ring heteroatoms independently selected from N,O, and S.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is 8-15 membered fused tricyclicheterocyclyl, wherein the 8-15 membered fused tricyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R¹is 8-15 membered fused tricyclic heterocyclyl, wherein the 8-15 memberedfused tricyclic heterocyclyl is optionally substituted with 1-3 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R¹ is 8-15 membered fusedtricyclic heterocyclyl, wherein the 8-15 membered fused tricyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₆ alkyl,and C₃₋₇ monocyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is 8-15 membered fused tricyclicheterocyclyl, wherein the 8-15 membered fused tricyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹ is 8-15membered fused tricyclic heterocyclyl, wherein the 8-15 membered fusedtricyclic heterocyclyl is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R¹ is 8-15 membered fused tricyclic heterocyclyl, whereinthe 8-15 membered fused tricyclic heterocyclyl is substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, C₁₋₆ alkyl, and C₃₋₇ monocyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is 8-15 membered fused tricyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is 8-15 membered fused tricyclic heteroaryl,wherein the 8-15 membered fused tricyclic heteroaryl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹ is 8-15membered fused tricyclic heteroaryl, wherein the 8-15 membered fusedtricyclic heteroaryl is optionally substituted with 1-3 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is 8-15 membered fused tricyclic heteroaryl,wherein the 8-15 membered fused tricyclic heteroaryl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₆ alkyl, and C₃₋₇ monocycliccycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is 8-15 membered fused tricyclic heteroaryl,wherein the 8-15 membered fused tricyclic heteroaryl is substituted with1-4 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R¹ is 8-15 membered fusedtricyclic heteroaryl, wherein the 8-15 membered fused tricyclicheteroaryl is substituted with 1-3 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,R¹ is 8-15 membered fused tricyclic heteroaryl, wherein the 8-15membered fused tricyclic heteroaryl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, C₁₋₆ alkyl, and C₃₋₇ monocyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is

which is optionally substituted with 1-3 groups independently selectedfrom halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 halogen groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is

wherein each R^(1a) independently is H, —CN, C₁₋₆ alkyl, C₁₋₅ alkoxy, orC₃₋₇ monocyclic cycloalkyl, wherein the C₁₋₆ alkyl and C₁₋₅ alkoxy areeach optionally substituted with 1-3 halogen groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(1a) independently is H, —CN, —CHF₂,—CF₃, methyl, methoxy, or cyclopropyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹ is

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-4 groups independently selected fromhalogen and C₁₋₆ alkoxy, wherein the C₁₋₆ alkoxy is optionallysubstituted with 1-3 halogen groups. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, R² is C₁₋₆alkyl, wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from halogen and C₁₋₆ alkoxy, wherein the C₁₋₆alkoxy is optionally substituted with 1-3 halogen groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from halogen and C₁₋₃alkoxy, wherein the C₁₋₃ alkoxy is optionally substituted with 1-3halogen groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R² is C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is substituted with 1-4 groups independently selected fromhalogen and C₁₋₆ alkoxy, wherein the C₁₋₆ alkoxy is optionallysubstituted with 1-3 halogen groups. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, R² is C₁₋₆alkyl, wherein the C₁₋₆ alkyl is substituted with 1-3 groupsindependently selected from halogen and C₁₋₆ alkoxy, wherein the C₁₋₆alkoxy is optionally substituted with 1-3 halogen groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is substitutedwith 1-3 groups independently selected from halogen and C₁₋₃ alkoxy,wherein the C₁₋₃ alkoxy is optionally substituted with 1-3 halogengroups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-4 groups independently selected fromhalogen and C₁₋₆ alkoxy. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R² is C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from halogen and C₁₋₆ alkoxy. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, R² is C₁₋₆alkyl, wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from halogen and C₁₋₃ alkoxy. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is substituted with1-4 groups independently selected from halogen and C₁₋₆ alkoxy. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is substitutedwith 1-3 groups independently selected from halogen and C₁₋₆ alkoxy. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R² is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl issubstituted with 1-3 groups independently selected from halogen and C₁₋₃alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R² is C₁₋₄ alkyl, wherein the C₁₋₄ alkyl isoptionally substituted with 1-4 groups independently selected fromhalogen and C₁₋₆ alkoxy. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R² is C₁₋₄ alkyl, whereinthe C₁₋₄ alkyl is optionally substituted with 1-3 groups independentlyselected from halogen and C₁₋₆ alkoxy. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, R² is C₁₋₄alkyl, wherein the C₁₋₄ alkyl is optionally substituted with 1-3 groupsindependently selected from halogen and C₁₋₃ alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R² is C₁₋₄ alkyl, wherein the C₁₋₄ alkyl issubstituted with 1-4 groups independently selected from halogen and C₁₋₆alkoxy. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R² is C₁₋₄ alkyl, wherein theC₁₋₄ alkyl is substituted with 1-3 groups independently selected fromhalogen and C₁₋₆ alkoxy. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R² is C₁₋₄ alkyl, whereinthe C₁₋₄ alkyl is substituted with 1-3 groups independently selectedfrom halogen and C₁₋₃ alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R² is C₁₋₆ alkyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R²is C₁₋₄ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R² is C₁₋₃ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R² is ethyl or isopropyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R²is methyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R² is ethyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R² is propyl. In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, R² is isopropyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is H, halogen, —CN, C₁₋₆ alkyl, and C₃₋₇monocyclic cycloalkyl,

-   -   wherein the C₁₋₆ alkyl and C₃₋₇ monocyclic cycloalkyl are each        independently optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, and C₁₋₄ alkoxy,        -   wherein the C₁₋₄ alkoxy is optionally substituted with 1-3            halogen groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is H or C₁₋₆ alkyl,

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, and C₁₋₄ alkoxy,        -   wherein the C₁₋₄ alkoxy is optionally substituted with 1-3            halogen groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkylis optionally substituted with 1-3 groups independently selected from—OH, halogen, —CN, and C₁₋₄ alkoxy. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R³ is H orC₁₋₆ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R³ is H or methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is H. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R³ is halogen.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is —CN.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, and C₁₋₄ alkoxy, whereinthe C₁₋₄ alkoxy is optionally substituted with 1-3 halogen groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, and C₁₋₄ alkoxy, wherein the C₁₋₄alkoxy is optionally substituted with 1-3 halogen groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R³ is C₃₋₇ monocyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, and C₁₋₄ alkoxy, wherein the C₁₋₄ alkoxy is optionallysubstituted with 1-3 halogen groups. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, R³ is C₁₋₆alkyl, wherein the C₁₋₆ alkyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, and C₁₋₄ alkoxy, whereinthe C₁₋₄ alkoxy is optionally substituted with 1-3 halogen groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, and C₁₋₄ alkoxy. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R³ is C₁₋₆alkyl, wherein the C₁₋₆ alkyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, and C₁₋₄ alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is C₁₋₄ alkyl optionally substituted with1-3 groups independently selected from —OH, halogen, —CN, and C₁₋₃alkoxy. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R³ is methyl substituted with1-3 halogen groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R³ is —CHF₂.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R³ is C₁₋₆ alkyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R³is C₁₋₄ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R³ is C₁₋₃ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R³ is methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₁₋₆ alkyl, —C(O)R¹³, —C(O)NR⁶R⁷, C₃₋₇monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridgedbicyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl, phenyl, 5-6membered monocyclic heteroaryl, 8-10 membered fused bicyclicheterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10 memberedfused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4 R^(b)        groups,    -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered        monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic        heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10        membered bridged bicyclic heterocyclyl, 8-10 membered fused        bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl        are each independently optionally substituted with 1-2 R⁸ groups        and are each independently optionally substituted with 1-3 R^(a)        groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₇₋₁₀ fused bicyclic cycloalkyl, 8-10membered fused bicyclic heterocyclyl, 6-10 membered bridged bicyclicheterocyclyl, or 8-10 membered fused bicyclic heteroaryl,

-   -   wherein the C₇₋₁₀ fused bicyclic cycloalkyl, 8-10 membered fused        bicyclic heterocyclyl, 6-10 membered bridged bicyclic        heterocyclyl, and 8-10 membered fused bicyclic heteroaryl are        each independently optionally substituted with 1-2 R⁸ groups and        are each independently optionally substituted with 1-3 R^(a)        groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 4-7 membered monocyclic heterocyclyl,phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclicheterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, or 7-10membered spirocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl, phenyl, 5-6        membered monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, and        7-10 membered spirocyclic heterocyclyl are each independently        optionally substituted with 1-2 R⁸ groups and are each        independently optionally substituted with 1-3 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 4-7 membered monocyclic heterocyclyl,phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclicheterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, or 7-10membered spirocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl, phenyl, 5-6        membered monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, and        7-10 membered spirocyclic heterocyclyl are each independently        optionally substituted with 1-2 R⁸ groups and are each        independently optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,        C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₇₋₁₀ fused bicyclic cycloalkyl, 8-10membered fused bicyclic heterocyclyl, 6-10 membered bridged bicyclicheterocyclyl, or 8-10 membered fused bicyclic heteroaryl,

-   -   wherein the C₇₋₁₀ fused bicyclic cycloalkyl, 8-10 membered fused        bicyclic heterocyclyl, 6-10 membered bridged bicyclic        heterocyclyl, and 8-10 membered fused bicyclic heteroaryl are        each independently optionally substituted with 1-2 R⁸ groups and        are each independently optionally substituted with 1-3 R^(a)        groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-4 R^(b) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with 1-3R^(b) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is substituted with 1-4 R^(b) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,Z is C₁₋₆ alkyl, wherein the C₁₋₁₀ alkyl is substituted with 1-3 R^(b)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is C₁₋₆ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is optionally substituted with 1-2 R⁸ groupsand is optionally substituted with 1-3 R^(a) groups. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, Z is C₃₋₇ monocyclic cycloalkyl, wherein the C₃₋₇ monocycliccycloalkyl is optionally substituted with 1-2 R⁸ groups and isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is substituted with 1-2 R⁸ groups and isoptionally substituted with 1-3 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis C₃₋₇ monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl issubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is substituted with 1-2 R⁸ groups and issubstituted with 1-3 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, Z is C₃₋₇monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl issubstituted with 1-2 R⁸ groups and is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is substituted with 1-2 R⁸ groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is C₃₋₇ monocyclic cycloalkyl, wherein the C₃₋₇monocyclic cycloalkyl is optionally substituted with 1-3 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, Z is C₃₋₇ monocycliccycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is cyclobutanyl, cyclopentanyl, orcyclohexanyl, each of which is optionally substituted with 1-2 R⁸ groupsand optionally substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is cyclobutanyl, cyclopentanyl, or cyclohexanyl, each ofwhich is substituted with 1-2 R⁸ groups and is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, —CN, oxo,—NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, Z iscyclobutanyl, cyclopentanyl, or cyclohexanyl, each of which isoptionally substituted with 1-2 R⁸ groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis cyclobutanyl, cyclopentanyl, or cyclohexanyl, each of which isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₇₋₁₀ fused bicyclic cycloalkyl, whereinthe C₇₋₁₀ fused bicyclic cycloalkyl is optionally substituted with 1-2R⁸ groups and is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀fused bicyclic cycloalkyl is substituted with 1-2 R⁸ groups and isoptionally substituted with 1-3 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀ fused bicycliccycloalkyl is substituted with 1-2 R⁸ groups and is substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is C₇₋₁₀ fused bicycliccycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkyl is substitutedwith 1-2 R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is C₇₋₁₀ fused bicycliccycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkyl is optionallysubstituted with 1-3 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, Z is C₇₋₁₀fused bicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is C₅₋₁₀ bridged bicyclic cycloalkyl, whereinthe C₅₋₁₀ bridged bicyclic cycloalkyl is optionally substituted with 1-2R⁸ groups and is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is C₅₋₁₀ bridged bicyclic cycloalkyl, wherein the C₅₋₁₀bridged bicyclic cycloalkyl is substituted with 1-2 R⁸ groups and isoptionally substituted with 1-3 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis C₅₋₁₀ bridged bicyclic cycloalkyl, wherein the C₅₋₁₀ bridged bicycliccycloalkyl is substituted with 1-2 R⁸ groups and is substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is C₅₋₁₀ bridged bicycliccycloalkyl, wherein the C₅₋₁₀ bridged bicyclic cycloalkyl is substitutedwith 1-2 R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is C₅₋₁₀ bridged bicycliccycloalkyl, wherein the C₅₋₁₀ bridged bicyclic cycloalkyl is optionallysubstituted with 1-3 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, Z is C₅₋₁₀bridged bicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl issubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl issubstituted with 1-2 R⁸ groups and is substituted with 1-3 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is substituted with 1-2R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-3 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis 4-7 membered monocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 5-6 membered monocyclicheterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl isoptionally substituted with 1-2 R⁸ groups and is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, —CN, oxo,—NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is substituted with 1-2R⁸ groups and is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is 5-6 membered monocyclic heterocyclyl, wherein the 5-6membered monocyclic heterocyclyl is substituted with 1-2 R⁸ groups andis optionally substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is substituted with 1-2R⁸ groups and is substituted with 1-3 R^(a) groups. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, Z is 5-6 membered monocyclic heterocyclyl, wherein the 5-6membered monocyclic heterocyclyl is substituted with 1-2 R⁸ groups andis substituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is substituted with 1-2R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 5-6 membered monocyclicheterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is 5-6 membered monocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is phenyl, wherein the phenyl is optionallysubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is phenyl, wherein thephenyl is optionally substituted with 1-2 R⁸ groups and is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is phenyl, wherein the phenyl is substitutedwith 1-2 R⁸ groups and is optionally substituted with 1-3 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is phenyl, wherein the phenyl is substitutedwith 1-2 R⁸ groups and is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is phenyl, wherein the phenyl is substitutedwith 1-2 R⁸ groups and is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is phenyl, wherein the phenyl is substituted with 1-2 R⁸groups and is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is phenyl, wherein the phenyl is substitutedwith 1-2 R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is phenyl, wherein thephenyl is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is phenyl, wherein the phenyl is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, —CN, oxo,—NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, Z isphenyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith 1-2 R⁸ groups and is optionally substituted with 1-3 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is substituted with 1-2R⁸ groups and is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is 5-6 membered monocyclic heteroaryl, wherein the 5-6membered monocyclic heteroaryl is substituted with 1-2 R⁸ groups and issubstituted with 1-3 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, Z is 5-6membered monocyclic heteroaryl, wherein the 5-6 membered monocyclicheteroaryl is substituted with 1-2 R⁸ groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis 5-6 membered monocyclic heteroaryl, wherein the 5-6 memberedmonocyclic heteroaryl is optionally substituted with 1-3 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith 1-2 R⁸ groups and is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is substituted with 1-2R⁸ groups and is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is substituted with 1-2R⁸ groups and is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, —CN, oxo,—NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heterocyclyl,wherein the 8-10 membered fused bicyclic heterocyclyl is optionallysubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 8-10 membered fusedbicyclic heterocyclyl, wherein the 8-10 membered fused bicyclicheterocyclyl is optionally substituted with 1-2 R⁸ groups and isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heterocyclyl,wherein the 8-10 membered fused bicyclic heterocyclyl is substitutedwith 1-2 R⁸ groups and is optionally substituted with 1-3 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heterocyclyl,wherein the 8-10 membered fused bicyclic heterocyclyl is substitutedwith 1-2 R⁸ groups and is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heterocyclyl,wherein the 8-10 membered fused bicyclic heterocyclyl is substitutedwith 1-2 R⁸ groups and is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is 8-10 membered fused bicyclic heterocyclyl, whereinthe 8-10 membered fused bicyclic heterocyclyl is substituted with 1-2 R⁸groups and is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heterocyclyl,wherein the 8-10 membered fused bicyclic heterocyclyl is substitutedwith 1-2 R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 8-10 membered fusedbicyclic heterocyclyl, wherein the 8-10 membered fused bicyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 8-10 membered fusedbicyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-2 R⁸ groups and is optionally substitutedwith 1-3 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, Z is 6-10 memberedbridged bicyclic heterocyclyl, wherein the 6-10 membered bridgedbicyclic heterocyclyl is optionally substituted with 1-2 R⁸ groups andis optionally substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is substituted with 1-2 R⁸ groups and is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-2 R⁸ groups and is substituted with 1-3 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-2 R⁸ groups and is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-2 R⁸ groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, Z is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, Z is 6-10 memberedbridged bicyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl,wherein the 8-10 membered fused bicyclic heteroaryl is optionallysubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 8-10 membered fusedbicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroarylis optionally substituted with 1-2 R⁸ groups and is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl,wherein the 8-10 membered fused bicyclic heteroaryl is substituted with1-2 R⁸ groups and is optionally substituted with 1-3 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl,wherein the 8-10 membered fused bicyclic heteroaryl is substituted with1-2 R⁸ groups and is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl,wherein the 8-10 membered fused bicyclic heteroaryl is substituted with1-2 R⁸ groups and is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is 8-10 membered fused bicyclic heteroaryl, wherein the8-10 membered fused bicyclic heteroaryl is substituted with 1-2 R⁸groups and is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heteroaryl,wherein the 8-10 membered fused bicyclic heteroaryl is substituted with1-2 R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 8-10 membered fusedbicyclic heteroaryl, wherein the 8-10 membered fused bicyclic heteroarylis optionally substituted with 1-3 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,Z is 8-10 membered fused bicyclic heteroaryl, wherein the 8-10 memberedfused bicyclic heteroaryl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, Z is 8-10 membered fusedbicyclic heteroaryl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is optionallysubstituted with 1-2 R⁸ groups and is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-2 R⁸ groups and is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, —CN, oxo,—NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is substituted with1-2 R⁸ groups and is optionally substituted with 1-3 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is substituted with1-2 R⁸ groups and is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is substituted with1-2 R⁸ groups and is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is 7-10 membered spirocyclic heterocyclyl, wherein the7-10 membered spirocyclic heterocyclyl is substituted with 1-2 R⁸ groupsand is substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is substituted with1-2 R⁸ groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, Z is 7-10 membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with one R⁸ group and optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with one R⁸ group and optionally substituted with        1-3 groups independently selected from —OH, halogen, —CN, oxo,        —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 4-7 membered monocyclic heterocyclyl has one or two        ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heterocyclyl,

-   -   wherein the 5-6 membered monocyclic heterocyclyl is optionally        substituted with one R⁸ groups and is optionally substituted        with 1-2 groups independently selected from —OH, halogen, —CN,        oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 5-6 membered monocyclic heterocyclyl has one or two        ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is piperidinyl, wherein the piperidinyl isoptionally substituted with one R⁸ group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is phenyl or 5-6 membered monocyclicheteroaryl, each of which is optionally substituted with one R⁸ groupand is optionally substituted with 1-2 groups independently selectedfrom —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is phenyl optionally substituted with one R⁸group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith one R⁸ group and has one, two, or three ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is pyridinyl or

each of which is optionally substituted with one R⁸ group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heterocyclyloptionally substituted with one R⁸ groups and is optionally substitutedwith 1-2 groups independently selected from —OH, halogen, —CN, oxo,—NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 8-10 membered fused bicyclic heterocyclyl,

-   -   wherein the 8-10 membered fused bicyclic heterocyclyl is        optionally substituted with one R⁸ groups and is optionally        substituted with 1-2 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 8-10 membered fused bicyclic heterocyclyl has one or        two ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is

each of which is optionally substituted with one R⁸ group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 6-10 membered bridged bicyclicheterocyclyl optionally substituted with one R⁸ groups and optionallysubstituted with 1-2 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 6-10 membered bridged bicyclicheterocyclyl,

-   -   wherein the 6-10 membered bridged bicyclic heterocyclyl is        optionally substituted with one R⁸ groups and is optionally        substituted with 1-2 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 6-10 membered bridged bicyclic heterocyclyl has one        or two ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is

each of which is optionally substituted with one R⁸ group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyloptionally substituted with one R⁸ group and optionally substituted with1-2 groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is 7-10 membered spirocyclic heterocyclyl,

-   -   wherein the 7-10 membered spirocyclic heterocyclyl is optionally        substituted with one R⁸ groups and is optionally substituted        with 1-2 groups independently selected from —OH, halogen, —CN,        oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 7-10 membered spirocyclic heterocyclyl has one or        two ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is

which is optionally substituted with one R⁸ group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is

which is optionally substituted with one R⁸ group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z substituted with one R⁸ group is

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R⁸ independently is halogen, —C(O)R⁹,—NR¹⁰R¹⁰, C₁₋₆ alkyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered monocyclicheterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-10 memberedfused bicyclic heterocyclyl, 6-10 membered bridged bicyclicheterocyclyl, 8-10 membered fused bicyclic heteroaryl, 7-10 memberedspirocyclic heterocyclyl, —OR⁵, —C(O)N(R⁵)(R⁵), —N(R⁵)₂(R⁵)⁺,—N(R⁵)C(O)R⁵, —N(R⁵)C(O)OR⁵, —N(R⁵)C(O)N(R⁵)(R⁵), —N(R⁵)S(O)₂(R^(5a)),—NR⁵S(O)₂N(R⁵)(R⁵), —NR⁵S(O)₂O(R^(5a)), —OC(O)N(R⁵)(R⁵), —S(O)R^(5a),—S(O)(NH)R⁵, —S(O)₂R^(5a), —S(O)₂N(R⁵)(R⁵), or —N═S(R^(5a))(R^(5a))═O,

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4 R^(b)        groups,    -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered        monocyclic heterocyclyl, phenyl, 5-6 membered monocyclic        heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10        membered bridged bicyclic heterocyclyl, 8-10 membered fused        bicyclic heteroaryl, and 7-10 membered spirocyclic heterocyclyl        are each independently optionally substituted with 1-4 R^(a)        groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R⁸ independently is —C(O)R⁹, C₁₋₆ alkyl,4-7 membered monocyclic heterocyclyl, or —S(O)₂R^(5a),

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-4 R^(b)        groups, and    -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R⁸ independently is —C(O)R⁹, C₁₋₆ alkyl,4-7 membered monocyclic heterocyclyl, or —S(O)₂R^(5a),

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,        —C(O)NR¹¹R¹¹, C₁₋₄ alkoxy, and R^(8a), and    -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is halogen. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or both R⁸ is —OR⁵. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or bothR^(B) is —C(O)N(R⁵)(R⁵). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁸ is—N(R⁵)₂(R⁵)⁺. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is—N(R⁵)C(O)R⁵. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is—N(R⁵)C(O)OR⁵. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is—N(R⁵)C(O)N(R⁵)(R⁵). In some embodiments of a compound of Formula I, ora pharmaceutically acceptable salt thereof, one or both R⁸ is—N(R⁵)S(O)₂(R^(5a)). In some embodiments of a compound of Formula I, ora pharmaceutically acceptable salt thereof, one or both R^(B) is—NR⁵S(O)₂N(R⁵)(R⁵). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is—NR⁵S(O)₂O(R^(5a)). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is—OC(O)N(R⁵)(R⁵). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is —S(O)R^(5a).In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is —S(O)(NH)R⁵. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is —S(O)₂N(R⁵)(R⁵). In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is —N═S(R^(5a))(R^(5a))═O.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1-4 R^(b) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-3 R^(b) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, —C(O)N(R¹¹)(R¹¹), C₁₋₄ alkoxy, and R^(8a). In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, —C(O)N(R¹¹)(R¹¹), C₁₋₄ alkoxy, and R^(8a).In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is C₁₋₃ alkyl, wherein the C₁₋₃alkyl is optionally substituted with 1-2 groups independently selectedfrom oxo, —NR¹¹R¹¹, —C(O)N(R¹¹)(R¹¹), and R^(8a). In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is substituted with1-4 R^(b) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is C₁₋₆ alkyl,wherein the C₁₋₆ alkyl is substituted with 1-3 R^(b) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl issubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, —C(O)N(R¹¹)(R¹¹), C₁₋₄ alkoxy, and R^(8a). In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl issubstituted with 1-3 groups independently selected from —OH, oxo, —NH₂,—N(CH₃)₂, —C(O)NH₂, —C(O)N(CH₃)₂, and R^(8a). In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is substituted with1-3 groups independently selected from —OH, oxo, —N(CH₃)₂, —C(O)NH₂, andR^(8a). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is C₁₋₃ alkyl,wherein the C₁₋₃ alkyl is substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, —C(O)N(R¹¹)(R¹¹), C₁₋₄alkoxy, and R^(8a). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is C₁₋₃ alkyl,wherein the C₁₋₃ alkyl is substituted with 1-2 groups independentlyselected from oxo, —NR¹¹R¹¹, —C(O)N(R¹¹)(R¹¹), and R^(8a). In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is C₁₋₆ alkyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆alkyl is substituted with 1-3 groups independently selected from —OH,oxo, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, and R^(8a). In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is substituted with 1-3 groupsindependently selected from —OH, oxo, —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃,and R^(8a).

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is C₃₋₇ monocyclic cycloalkyl,wherein the C₃₋₇ monocyclic cycloalkyl is optionally substituted with1-4 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is C₃₋₇monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is C₃₋₇ monocyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is C₇₋₁₀ fused bicycliccycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀ fused bicycliccycloalkyl is substituted with 1-4 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is C₇₋₁₀ fused bicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is C₅₋₁₀ bridged bicycliccycloalkyl, wherein the C₅₋₁₀ bridged bicyclic cycloalkyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is C₅₋₁₀ bridged bicyclic cycloalkyl, wherein the C₅₋₁₀ bridged bicycliccycloalkyl is substituted with 1-4 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is C₅₋₁₀ bridged bicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7membered monocyclic heterocyclyl is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is 4-7 memberedmonocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 memberedmonocyclic heterocyclyl is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 4-7 membered monocyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 5-6 membered monocyclicheterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is 5-6 membered monocyclic heterocyclyl, wherein the 5-6membered monocyclic heterocyclyl is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is 5-6 memberedmonocyclic heterocyclyl, wherein the 5-6 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 5-6 membered monocyclicheterocyclyl, wherein the 5-6 membered monocyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is 5-6 membered monocyclic heterocyclyl, wherein the 5-6 memberedmonocyclic heterocyclyl is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 5-6 membered monocyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is phenyl, wherein the phenyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is phenyl, wherein the phenyl is substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is phenyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 5-6 membered monocyclicheteroaryl, wherein the 5-6 membered monocyclic heteroaryl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is 5-6 membered monocyclic heteroaryl, wherein the 5-6 memberedmonocyclic heteroaryl is substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is 5-6 membered monocyclic heteroaryl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is 8-10 membered fused bicyclic heterocyclyl, wherein the8-10 membered fused bicyclic heterocyclyl is optionally substituted with1-3 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is 8-10 membered fused bicyclic heterocyclyl, wherein the 8-10 memberedfused bicyclic heterocyclyl is substituted with 1-3 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl issubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 8-10 membered fused bicyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-3 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is 6-10 membered bridged bicyclic heterocyclyl, whereinthe 6-10 membered bridged bicyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is substituted with 1-4 R^(a) groups. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or both R⁸ is 6-10 membered bridged bicyclic heterocyclyl,wherein the 6-10 membered bridged bicyclic heterocyclyl is substitutedwith 1-3 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁸ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 6-10 membered bridgedbicyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 7-8 membered bridged bicyclicheterocyclyl, wherein the 7-8 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is 7-8 membered bridged bicyclic heterocyclyl, whereinthe 7-8 membered bridged bicyclic heterocyclyl is optionally substitutedwith 1-3 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁸ is 7-8membered bridged bicyclic heterocyclyl, wherein the 7-8 membered bridgedbicyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 7-8 membered bridged bicyclicheterocyclyl, wherein the 7-8 membered bridged bicyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁸is 7-8 membered bridged bicyclic heterocyclyl, wherein the 7-8 memberedbridged bicyclic heterocyclyl is substituted with 1-3 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 7-8 membered bridged bicyclicheterocyclyl, wherein the 7-8 membered bridged bicyclic heterocyclyl issubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 7-8 membered bridged bicyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁸ is 7-10 membered spirocyclic heterocyclyl, wherein the7-10 membered spirocyclic heterocyclyl is substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is 7-10membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is substituted with1-3 groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from oxoand methyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁸ is 7-10membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclicheterocyclyl is substituted with 1-3 groups independently selected fromoxo and methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is

each of which is optionally substituted with one methyl group. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁸ is

each of which is substituted with one methyl group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 4-7 membered monocyclic heterocyclyl has one or two        ring heteroatoms independently selected from N and S.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-2 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is piperidinyl or piperazinyl, each of whichis optionally substituted with 1-2 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is piperidinyl or piperazinyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, —C(O)NR¹¹R¹¹, C₁₋₄ alkoxy, and R^(8a).

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl issubstituted with 1-2 groups independently selected from —C(O)NR¹¹R¹¹ andR^(8a).

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is C₁₋₄ alkyl, wherein the C₁₋₄ alkyl issubstituted with 1-2 groups independently selected from —C(O)NH₂, 4-7membered monocyclic heterocyclyl, and 5-6 membered monocyclicheteroaryl, and

-   -   wherein the 4-7 membered monocyclic heterocyclyl and 5-6        membered monocyclic heteroaryl are each independently optionally        substituted with one group selected from —OH, halogen, C₁₋₃        alkoxy, and C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(8a) independently is 4-7 memberedmonocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, whereinthe 4-7 membered monocyclic heterocyclyl and 5-6 membered monocyclicheteroaryl are each independently optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(8a) independently is 4-memberedmonocyclic heterocyclyl or 5-membered monocyclic heteroaryl, each ofwhich is optionally substituted with one C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(8a) independently is oxetanyl or5-membered monocyclic heteroaryl having two ring heteroatoms that is N,and wherein the oxetanyl and the 5-membered monocyclic heteroaryl areeach optionally substituted with methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(8a) independently is oxetanyl orpyrazolyl, wherein the oxetanyl and pyrazolyl are each optionallysubstituted with methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is —C(O)R⁹. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, R⁸ is —C(O)R⁹.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R⁹ independently is C₃₋₇ monocycliccycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicycliccycloalkyl, phenyl, naphthalenyl, 4-7 membered monocyclic heterocyclyl,5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclicheterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10 memberedfused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl,

-   -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, and 7-10 membered        spirocyclic heterocyclyl are each independently optionally        substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R⁹ independently is C₃₋₇ monocycliccycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein the C₃₋₇monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are eachindependently optionally substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R⁹ independently is C₃₋₇ monocycliccycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein the C₃₋₇monocyclic cycloalkyl and 4-7 membered monocyclic heterocyclyl are eachindependently optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₅ alkyl,and 4-7 membered monocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is C₃₋₇ monocyclic cycloalkyl,wherein the C₃₋₇ monocyclic cycloalkyl is optionally substituted with1-4 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is C₃₋₇monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₅ alkyl, and 4-7 memberedmonocyclic heterocyclyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁹ is C₃₋₇monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁹is C₃₋₇ monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl issubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₅ alkyl, and 4-7 membered monocyclicheterocyclyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is C₃₋₇monocyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is C₇₋₁₀ fused bicycliccycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁹is C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀ fused bicycliccycloalkyl is substituted with 1-4 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is C₇₋₁₀ fused bicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is C₅₋₁₀ bridged bicycliccycloalkyl, wherein the C₅₋₁₀ bridged bicyclic cycloalkyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁹is C₅₋₁₀ bridged bicyclic cycloalkyl, wherein the C₅₋₁₀ bridged bicycliccycloalkyl is substituted with 1-4 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is C₅₋₁₀ bridged bicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is phenyl, wherein the phenyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is phenyl, wherein the phenyl is substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is phenyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is naphthalenyl, wherein thenaphthalenyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁹ is naphthalenyl, wherein the naphthalenylis substituted with 1-4 R^(a) groups. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, one or bothR⁹ is naphthalenyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 5-6 membered monocyclicheteroaryl, wherein the 5-6 membered monocyclic heteroaryl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁹is 5-6 membered monocyclic heteroaryl, wherein the 5-6 memberedmonocyclic heteroaryl is substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁹ is 5-6 membered monocyclic heteroaryl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is 8-10 membered fused bicyclic heterocyclyl, wherein the8-10 membered fused bicyclic heterocyclyl is substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is 8-10membered fused bicyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 8-10 membered fused bicyclicheteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is 8-10 membered fused bicyclic heteroaryl, wherein the8-10 membered fused bicyclic heteroaryl is substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is 8-10membered fused bicyclic heteroaryl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is 7-10 membered spirocyclic heterocyclyl, wherein the7-10 membered spirocyclic heterocyclyl is substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is 7-10membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl has 1-2ring heteroatoms independently selected from N and O.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, C₁₋₅ alkyl, and 4-7 membered monocyclic heterocyclyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or both R⁹is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 memberedmonocyclic heterocyclyl is substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₅ alkyl,and 4-7 membered monocyclic heterocyclyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is 4-7 membered monocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 5-7 membered monocyclicheterocyclyl, wherein the 5-7 membered monocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is 5-7 membered monocyclic heterocyclyl, wherein the 5-7membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃alkoxy, and C₁₋₃ alkyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁹ is 5-7membered monocyclic heterocyclyl, wherein the 5-7 membered monocyclicheterocyclyl is substituted with 1-4 R^(a) groups. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or both R⁹ is 5-7 membered monocyclic heterocyclyl, whereinthe 5-7 membered monocyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy,and C₁₋₃ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is 5-7 memberedmonocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 4-6 membered monocyclicheterocyclyl, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R⁹ is 4-6 membered monocyclic heterocyclyl, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃alkoxy, and C₁₋₃ alkyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁹ is 4-6membered monocyclic heterocyclyl, wherein the 4-6 membered monocyclicheterocyclyl is optionally substituted with 1-2 groups independentlyselected from —OH, halogen, C₁₋₃ alkoxy, and C₁₋₃ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁹ is 4-6 membered monocyclic heterocyclyl,wherein the 4-6 membered monocyclic heterocyclyl is substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is 4-6 memberedmonocyclic heterocyclyl, wherein the 4-6 membered monocyclicheterocyclyl is substituted with 1-3 groups independently selected from—OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy, and C₁₋₃ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁹ is 4-6 membered monocyclic heterocyclyl,wherein the 4-6 membered monocyclic heterocyclyl is substituted with 1-2groups independently selected from —OH, halogen, C₁₋₃ alkoxy, and C₁₋₃alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is 4-6 memberedmonocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁹ is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁹ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R⁹ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy, and C₁₋₃ alkyl. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or both R⁹ is 6-10 membered bridged bicyclic heterocyclyl,wherein the 6-10 membered bridged bicyclic heterocyclyl is substitutedwith 1-4 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁹ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or both R⁹ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy,and C₁₋₃ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R⁹ is 6-10membered bridged bicyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₅ alkyl, and 4-7 membered monocyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 4-7 membered monocyclic heterocyclyl has one or two        ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-2 groups independently selected from —OH, halogen,C₁₋₃ alkoxy, and C₁₋₃ alkyl, and wherein the 5-6 membered monocyclicheterocyclyl has one or two ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is pyrrolidinyl or morpholinyl, each ofwhich is optionally substituted with 1-2 groups independently selectedfrom —OH, halogen, C₁₋₃ alkoxy, and C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is azetidinyl or pyrrolidinyl, each of whichis optionally substituted with 1-2 groups independently selected from—OH, halogen, C₁₋₃ alkoxy, and C₁₋₃ alkyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R⁹is azetidinyl or pyrrolidinyl, each of which is substituted with 1-2groups independently selected from —OH, halogen, C₁₋₃ alkoxy, and C₁₋₃alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is

each of which is optionally substituted with 1-2 groups independentlyselected from —OH, methyl, and trifluoromethyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R⁹is

each of which is substituted with 1-2 groups independently selected from—OH, methyl, and trifluoromethyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₁₋₅ alkyl, and 4-7 membered monocyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is cyclopropyl, cyclobutyl, orcyclopentanyl, each of which is optionally substituted with 1-2 groupsindependently selected from —OH, halogen, C₁₋₃ alkoxy, C₁₋₃ alkyl, and4-7 membered monocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is cyclopropyl, cyclobutyl, orcyclopentanyl, each of which is optionally substituted with 1-2 groupsindependently selected from —OH, halogen, C₁₋₃ alkoxy, C₁₋₃ alkyl, and5-7 membered monocyclic heterocyclyl, wherein the 5-7 memberedmonocyclic heterocyclyl has one or two ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is cyclopropyl optionally substituted with 6membered monocyclic heterocyclyl, wherein the 6 membered monocyclicheterocyclyl has one ring heteroatom that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁹ is cyclopropyl optionally substituted withmorpholinyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is —NR¹⁰R¹⁰.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R⁸ is —S(O)₂R^(5a).

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁸ is —S(O)₂R^(5a).

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R^(5a) is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 4-7 membered monocyclic heterocyclyl has one or two        ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R^(5a) is 5-6 membered monocyclic heterocyclyl,

-   -   wherein the 5-6 membered heterocyclyl is optionally substituted        with 1-2 groups independently selected from —OH, halogen, —CN,        and C₁₋₅ alkyl, and    -   wherein the 5-6 membered heterocyclyl has one or two ring        heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R^(5a) is piperazinyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is —C(O)NR⁶R⁷. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, Zis —C(O)N(H)R⁶. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, Z is —C(O)N(CH₃)R⁶.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fusedbicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 memberedmonocyclic heterocyclyl, 8-10 membered fused bicyclic heterocyclyl, 6-10membered bridged bicyclic heterocyclyl or 7-10 membered spirocyclicheterocyclyl,

-   -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, 4-7 membered        monocyclic heterocyclyl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, and        7-10 membered spirocyclic heterocyclyl are each independently        optionally substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3 R^(b)        groups,    -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-2 groups        independently selected from —OH, halogen, —NR¹¹R¹¹, and C₁₋₃        alkoxy,    -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy, and C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and

-   -   wherein the C₁₋₄ alkoxy and C₁₋₅ alkyl are each independently        optionally substituted with 1-3 groups independently selected        from —OH, halogen, —CN, and —NR¹²R¹².

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,R⁶ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 memberedmonocyclic heterocyclyl is substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is optionally substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁶ is C₃₋₇ monocycliccycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl is substituted with1-4 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁶ is C₃₋₇ monocycliccycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is C₇₋₁₀ fused bicyclic cycloalkyl, whereinthe C₇₋₁₀ fused bicyclic cycloalkyl is optionally substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁶ is C₇₋₁₀ fused bicycliccycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkyl is substitutedwith 1-4 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R⁶ is C₇₋₁₀ fusedbicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is C₅₋₁₀ bridged bicyclic cycloalkyl,wherein the C₅₋₁₀ bridged bicyclic cycloalkyl is optionally substitutedwith 1-4 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R⁶ is C₅₋₁₀ bridgedbicyclic cycloalkyl, wherein the C₅₋₁₀ bridged bicyclic cycloalkyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁶ is C₅₋₁₀bridged bicyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁶ is 4-7membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl, wherein the4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₄ alkoxy and C₁₋₅ alkyl areeach independently optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, and —NR¹²R¹². In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R⁶is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 memberedmonocyclic heterocyclyl is optionally substituted 1-3 groupsindependently selected from —OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy,and C₁₋₃ alkyl, wherein the C₁₋₃ alkoxy and C₁₋₃ alkyl are eachindependently optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, and —NR¹²R¹². In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R⁶is 5-6 membered monocyclic heterocyclyl, wherein the 5-6 memberedmonocyclic heterocyclyl is optionally substituted 1-3 groupsindependently selected from —OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy,and C₁₋₃ alkyl, wherein the C₁₋₃ alkoxy and C₁₋₃ alkyl are eachindependently optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, and —NR¹²R¹².

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁶ is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl issubstituted with 1-3 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁶ is 4-7membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, whereinthe C₁₋₄ alkoxy and C₁₋₅ alkyl are each independently optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, and —NR¹²R¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁶ is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl issubstituted with 1-3 groups independently selected from —OH, halogen,—CN, —NR¹¹R¹¹, C₁₋₃ alkoxy, and C₁₋₃ alkyl, wherein the C₁₋₃ alkoxy andC₁₋₃ alkyl are each independently optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, and —NR¹²R¹². In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R⁶ is 5-6 membered monocyclic heterocyclyl, wherein the5-6 membered monocyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, —NR¹¹R¹¹, C₁₋₃ alkoxy,and C₁₋₃ alkyl, wherein the C₁₋₃ alkoxy and C₁₋₃ alkyl are eachindependently optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, and —NR¹²R¹²

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 5-6 membered monocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl,        wherein the C₁₋₄ alkoxy and C₁₋₅ alkyl are each independently        optionally substituted with 1-3 groups independently selected        from —OH, halogen, —CN, and —NR¹²R¹², and    -   wherein the 4-7 membered monocyclic heterocyclyl has one or two        ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 5-6 membered monocyclic heterocyclyl,

-   -   wherein the 5-6 membered heterocyclyl is optionally substituted        with 1-2 groups independently selected from —OH, halogen, —CN,        and C₁₋₅ alkyl, and    -   wherein the C₁₋₅ alkyl is optionally substituted with 1-2 groups        independently selected from —OH and halogen.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is pyrrolidinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with 1-2 groupsindependently selected from —OH, halogen, —CN, and C₁₋₅ alkyl, whereinthe C₁₋₅ alkyl is optionally substituted with 1-2 groups independentlyselected from —OH and halogen.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is pyrrolidinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one C₁₋₃ alkylgroup, wherein the C₁₋₃ alkyl is optionally substituted with 1-2 groupsindependently selected from —OH and halogen.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is

each of which is optionally substituted with C₁₋₃ alkyl, wherein theC₁₋₃ alkyl is substituted with one —OH group.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is piperidinyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R⁶is 8-10 membered fused bicyclic heterocyclyl, wherein the 8-10 memberedfused bicyclic heterocyclyl is optionally substituted with 1-3 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁶ is 8-10 membered fusedbicyclic heterocyclyl, wherein the 8-10 membered fused bicyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁶ is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R⁶ is 8-10 membered fused bicyclic heterocyclyl, whereinthe 8-10 membered fused bicyclic heterocyclyl is substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 8-10 membered fused bicyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R⁶is 6-10 membered bridged bicyclic heterocyclyl, wherein the 6-10membered bridged bicyclic heterocyclyl is optionally substituted with1-3 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁶ is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁶ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is substituted with 1-3 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 6-10 membered bridged bicyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁶ is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁶ is 7-10membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclicheterocyclyl is substituted with 1-4 R^(a) groups. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, R⁶ is 7-10 membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁷ is H, C₁₋₆ alkyl, C₃₋₇ monocycliccycloalkyl, or 4-6 membered monocyclic heterocyclyl, wherein the C₁₋₆alkyl, C₃₋₇ monocyclic cycloalkyl, and 4-6 membered monocyclicheterocyclyl are each independently optionally substituted with 1-4groups independently selected from —OH, halogen, —CN, and C₁₋₆ alkoxy.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁷ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkylis optionally substituted with 1-4 groups independently selected from—OH, halogen, —CN, and C₁₋₆ alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁷ is H or C₁₋₃ alkyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof, R⁷is H or methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁷ is H.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁷ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-4 groups independently selected from —OH,halogen, —CN, and C₁₋₆ alkoxy. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁷ is C₁₋₆alkyl, wherein the C₁₋₆ alkyl is substituted with 1-4 groupsindependently selected from —OH, halogen, —CN, and C₁₋₆ alkoxy. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R⁷ is C₁₋₆ alkyl. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁷ is C₁₋₃alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R⁷ is methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁷ is C₃₋₇ monocyclic cycloalkyl, wherein theC₃₋₇ monocyclic cycloalkyl is optionally substituted with 1-4 groupsindependently selected from —OH, halogen, —CN, and C₁₋₆ alkoxy. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R⁷ is C₃₋₇ monocyclic cycloalkyl, wherein the C₃₋₇monocyclic cycloalkyl is substituted with 1-4 groups independentlyselected from —OH, halogen, —CN, and C₁₋₆ alkoxy. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,R⁷ is C₃₋₇ monocyclic cycloalkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R⁷ is 4-6 membered monocyclic heterocyclyl,wherein the 4-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-4 groups independently selected from —OH, halogen,—CN, and C₁₋₆ alkoxy. In some embodiments of a compound of Formula I, ora pharmaceutically acceptable salt thereof, R⁷ is 4-6 memberedmonocyclic heterocyclyl, wherein the 4-6 membered monocyclicheterocyclyl is substituted with 1-4 groups independently selected from—OH, halogen, —CN, and C₁₋₆ alkoxy. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁷ is 4-6membered monocyclic heterocyclyl. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R⁷ isoxetanyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, Z is —C(O)R¹³.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclicheterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10 memberedfused bicyclic heteroaryl, or 7-10 membered spirocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, and 7-10 membered        spirocyclic heterocyclyl are each independently optionally        substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, or 7-10 membered spirocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl, 8-10 membered        fused bicyclic heterocyclyl, 6-10 membered bridged bicyclic        heterocyclyl, and 7-10 membered spirocyclic heterocyclyl are        each independently optionally substituted with 1-3 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, or 7-10 membered spirocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl, 8-10 membered        fused bicyclic heterocyclyl, 6-10 membered bridged bicyclic        heterocyclyl, and 7-10 membered spirocyclic heterocyclyl are        each independently optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,        C₁₋₄ alkoxy, and C₁₋₅ alkyl,        -   wherein the C₁₋₅ alkyl is optionally substituted with 1-3            groups independently selected from —OH, halogen, —CN, oxo,            and —NR¹²R¹².

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, or 7-10 membered spirocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl, 8-10 membered        fused bicyclic heterocyclyl, 6-10 membered bridged bicyclic        heterocyclyl, and 7-10 membered spirocyclic heterocyclyl are        each independently optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,        C₁₋₄ alkoxy, and C₁₋₅ alkyl,        -   wherein the C₁₋₅ alkyl is optionally substituted with 1-2            groups independently selected from —OH, halogen, —CN, and            —NR¹²R¹², and        -   wherein each R¹² independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹³ is 4-7membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl, wherein the4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₅ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, and —NR¹²R¹². In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R¹³ is 4-7 memberedmonocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl, wherein the C₁₋₅ alkyl is optionally substituted with 1-2 groupsindependently selected from —OH, halogen, —CN, oxo, and —NR¹²R¹², andwherein each R¹² independently is H or C₁₋₃ alkyl. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, R¹³ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R¹³ is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl issubstituted with 1-3 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹³ is 4-7membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, whereinthe C₁₋₅ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, and —NR¹²R¹². In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, R¹³ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7membered monocyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₅ alkyl is optionally substitutedwith 1-2 groups independently selected from —OH, halogen, —CN, oxo, and—NR¹²R¹², and wherein each R¹² independently is H or C₁₋₃ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl, wherein the4-7 membered monocyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,R¹³ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 memberedmonocyclic heterocyclyl is substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl,

-   -   wherein the 4-7 membered monocyclic heterocyclyl is optionally        substituted with 1-3 groups independently selected from —OH,        halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, and    -   wherein the 4-7 membered monocyclic heterocyclyl has one or two        ring heteroatoms that is N.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 5-6 membered monocyclic heterocyclyl,wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 4-7 membered monocyclic heterocyclyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 5-6 membered monocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is piperazinyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith 1-4 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R¹³ is 5-6 memberedmonocyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹³ is 5-6membered monocyclic heteroaryl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,R¹³ is 8-10 membered fused bicyclic heterocyclyl, wherein the 8-10membered fused bicyclic heterocyclyl is optionally substituted with 1-3R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R¹³ is 8-10 membered fusedbicyclic heterocyclyl, wherein the 8-10 membered fused bicyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl, wherein the C₁₋₅ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, and —NR¹²R¹². Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, wherein theC₁₋₅ alkyl is optionally substituted with 1-2 groups independentlyselected from —OH, halogen, —CN, oxo, and —NR¹²R¹², and wherein each R¹²independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 8-10 membered fused bicyclicheterocyclyl, wherein the 8-10 membered fused bicyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹³ is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R¹³ is 8-10 membered fused bicyclic heterocyclyl, whereinthe 8-10 membered fused bicyclic heterocyclyl is substituted with 1-3groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₅ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, and —NR¹²R¹². In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R¹³ is 8-10 memberedfused bicyclic heterocyclyl, wherein the 8-10 membered fused bicyclicheterocyclyl is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, whereinthe C₁₋₅ alkyl is optionally substituted with 1-2 groups independentlyselected from —OH, halogen, —CN, oxo, and —NR¹²R¹², and wherein each R¹²independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 8-10 membered fused bicyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,R¹³ is 6-10 membered bridged bicyclic heterocyclyl, wherein the 6-10membered bridged bicyclic heterocyclyl is optionally substituted with1-3 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R¹³ is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl, wherein the C₁₋₅ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, and —NR¹²R¹². Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, wherein theC₁₋₅ alkyl is optionally substituted with 1-2 groups independentlyselected from —OH, halogen, —CN, oxo, and —NR¹²R¹², and wherein each R¹²independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹³ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is substituted with 1-3 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 6-10 membered bridged bicyclicheterocyclyl, wherein the 6-10 membered bridged bicyclic heterocyclyl issubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₅ alkylis optionally substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, and —NR¹²R¹². In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, R¹³ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₅ alkyl is optionally substitutedwith 1-2 groups independently selected from —OH, halogen, —CN, oxo, and—NR¹²R¹², and wherein each R¹² independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 6-10 membered bridged bicyclicheterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, R¹³ is 7-10membered spirocyclic heterocyclyl, wherein the 7-10 membered spirocyclicheterocyclyl is optionally substituted with 1-3 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, R¹³ is 7-10 membered spirocyclic heterocyclyl, wherein the7-10 membered spirocyclic heterocyclyl is optionally substituted with1-3 groups independently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹,C₁₋₄ alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₅ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, oxo, and —NR¹²R¹². In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, R¹³ is 7-10 memberedspirocyclic heterocyclyl, wherein the 7-10 membered spirocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅alkyl, wherein the C₁₋₅ alkyl is optionally substituted with 1-2 groupsindependently selected from —OH, halogen, —CN, oxo, and —NR¹²R¹², andwherein each R¹² independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 7-10 membered spirocyclic heterocyclyl,wherein the 7-10 membered spirocyclic heterocyclyl is substituted with1-4 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R¹³ is 7-10 memberedspirocyclic heterocyclyl, wherein the 7-10 membered spirocyclicheterocyclyl is substituted with 1-3 R^(a) groups. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, R¹³ is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10membered spirocyclic heterocyclyl is substituted with 1-3 groupsindependently selected from —OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄alkoxy, and C₁₋₅ alkyl, wherein the C₁₋₅ alkyl is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, —CN, oxo, and—NR¹²R¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, R¹³ is 7-10 memberedspirocyclic heterocyclyl, wherein the 7-10 membered spirocyclicheterocyclyl is substituted with 1-3 groups independently selected from—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, and C₁₋₅ alkyl, whereinthe C₁₋₅ alkyl is optionally substituted with 1-2 groups independentlyselected from —OH, halogen, —CN, oxo, and —NR¹²R¹², and wherein each R¹²independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, R¹³ is 7-10 membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R⁵ independently is H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10membered spirocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each        independently optionally substituted with 1-4 R^(b) groups,    -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, and 7-10 membered        spirocyclic heterocyclyl are each independently optionally        substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R⁵ is H. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R⁵ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-4 R^(b) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or more R⁵is C₂₋₆ alkenyl, wherein the C₂₋₆ alkenyl is optionally substituted with1-4 R^(b) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R⁵ is C₂₋₆alkynyl, wherein the C₂₋₆ alkynyl is optionally substituted with 1-4R^(b) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R⁵ is C₃₋₇monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R⁵ is C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀fused bicyclic cycloalkyl is optionally substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R⁵ is C₅₋₁₀bridged bicyclic cycloalkyl, wherein the C₅₋₁₀ bridged bicycliccycloalkyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R⁵ is phenyl, wherein the phenyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or more R⁵is naphthalenyl, wherein the naphthalenyl is optionally substituted with1-4 R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R⁵ is 4-7 memberedmonocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R⁵ is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith 1-4 R^(a) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R⁵ is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is optionally substituted with 1-4 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R⁵ is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R⁵ is 8-10 membered fused bicyclic heteroaryl,wherein the 8-10 membered fused bicyclic heteroaryl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or more R⁵is 7-10 membered spirocyclic heterocyclyl, wherein the 7-10 memberedspirocyclic heterocyclyl is optionally substituted with 1-4 R^(a)groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹⁰ independently is H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10membered spirocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each        independently optionally substituted with 1-4 R^(b) groups,    -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, and 7-10 membered        spirocyclic heterocyclyl are each independently optionally        substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹⁰ independently is H or C₁₋₆ alkyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹⁰ independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁰ is H. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R¹⁰ is C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-4 R^(b) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or bothR¹⁰ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1-4 R^(b) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R¹⁰ is C₁₋₃ alkyl.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁰ is C₂₋₆ alkenyl, wherein theC₂₋₆ alkenyl is optionally substituted with 1-4 R^(b) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or both R¹⁰ is C₂₋₆ alkynyl, wherein the C₂₋₆ alkynylis optionally substituted with 1-4 R^(b) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R¹⁰ is C₃₋₇ monocyclic cycloalkyl, wherein the C₃₋₇monocyclic cycloalkyl is optionally substituted with 1-4 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁰ is C₇₋₁₀ fused bicycliccycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or bothR¹⁰ is C₅₋₁₀ bridged bicyclic cycloalkyl, wherein the C₅₋₁₀ bridgedbicyclic cycloalkyl is optionally substituted with 1-4 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁰ is phenyl, wherein the phenylis optionally substituted with 1-4 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or both R¹⁰ is naphthalenyl, wherein the naphthalenyl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or bothR¹⁰ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 memberedmonocyclic heterocyclyl is optionally substituted with 1-4 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁰ is 5-6 membered monocyclicheteroaryl, wherein the 5-6 membered monocyclic heteroaryl is optionallysubstituted with 1-4 R^(a) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or bothR¹⁰ is 8-10 membered fused bicyclic heterocyclyl, wherein the 8-10membered fused bicyclic heterocyclyl is optionally substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R¹⁰ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is optionally substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or both R¹⁰ is 8-10membered fused bicyclic heteroaryl, wherein the 8-10 membered fusedbicyclic heteroaryl is optionally substituted with 1-4 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁰ is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(5a) independently is C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10membered spirocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each        independently optionally substituted with 1-4 R^(b) groups,    -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, and 7-10 membered        spirocyclic heterocyclyl are each independently optionally        substituted with 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(5a) is C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with 1-4 R^(b) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(5a) is C₂₋₆ alkenyl, wherein the C₂₋₆alkenyl is optionally substituted with 1-4 R^(b) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(5a) is C₂₋₆ alkynyl, wherein the C₂₋₆alkynyl is optionally substituted with 1-4 R^(b) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(5a) is C₃₋₇ monocyclic cycloalkyl, whereinthe C₃₋₇ monocyclic cycloalkyl is optionally substituted with 1-4 R^(a)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(5a) is C₇₋₁₀fused bicyclic cycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkylis optionally substituted with 1-4 R^(a) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(5a) is C₅₋₁₀ bridged bicyclic cycloalkyl, wherein theC₅₋₁₀ bridged bicyclic cycloalkyl is optionally substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(5a) is phenyl,wherein the phenyl is optionally substituted with 1-4 R^(a) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(5a) is naphthalenyl, wherein thenaphthalenyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(5a) is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(5a) is 5-6 membered monocyclic heteroaryl, wherein the5-6 membered monocyclic heteroaryl is optionally substituted with 1-4R^(a) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(5a) is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is optionally substituted with 1-4 R^(a) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(5a) is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-4 R^(a) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(5a) is 8-10 membered fused bicyclicheteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl isoptionally substituted with 1-4 R^(a) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(5a) is 7-10 membered spirocyclic heterocyclyl, whereinthe 7-10 membered spirocyclic heterocyclyl is optionally substitutedwith 1-4 R^(a) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(a) independently is oxo, imino,halogen, —NO₂, —N₃, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridgedbicyclic cycloalkyl, phenyl, naphthalenyl, 4-7 membered monocyclicheterocyclyl, 5-6 membered monocyclic heteroaryl, 8-10 membered fusedbicyclic heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10membered fused bicyclic heteroaryl, 7-10 membered spirocyclicheterocyclyl, —OR¹¹, —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹,—N(R¹¹)₂(R¹¹)⁺, —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹),—N(R¹¹)S(O)₂(R^(11a)), —NR¹¹S(O)₂N(R¹¹)(R¹¹), —NR¹¹S(O)₂O(R^(11a)),—OC(O)R¹¹, —OC(O)OR¹¹, —OC(O)N(R¹¹)(R¹¹), —SR¹¹, —S(O)R^(11a),—S(O)(NH)R¹¹, —S(O)₂R^(11a), —S(O)₂N(R¹¹)(R¹¹), or—N═S(R^(11a))(R^(11a))═O,

-   -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each        independently optionally substituted with 1-3 R^(c) groups, and    -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, and 7-10 membered        spirocyclic heterocyclyl are each independently optionally        substituted with 1-3 R^(d) groups.

In some embodiments of a compound of Formula I or II, or apharmaceutically acceptable salt thereof, each R^(a) independently is—OH, halogen, —CN, oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, or C₁₋₅ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, each R^(a) independently is —OH, halogen, —CN, oxo,—NR¹¹R¹¹, C₁₋₃ alkoxy, or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is oxo. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(a) is imino. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, one or moreR^(a) is halogen. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) is —NO₂. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is —N₃. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(a) is —CN. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(a) is —OR¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) is —C(O)R¹¹.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is —C(O)OR¹¹. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(a) is —C(O)N(R¹¹)(R¹¹). In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(a) is —NR¹¹R¹¹. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(a) is —N(R¹¹)₂(R¹¹). In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(a) is —N(R¹¹)C(O)R¹¹. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(a) is—N(R¹¹)C(O)OR¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) is—N(R¹¹)C(O)N(R¹¹)(R¹¹). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(a) is—N(R¹¹)S(O)₂(R^(11a)). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(a) is—NR¹¹S(O)₂N(R¹¹)(R¹¹). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(a) is—NR¹¹S(O)₂O(R^(11a)). In some embodiments of a compound of Formula I, ora pharmaceutically acceptable salt thereof, one or more R^(a) is—OC(O)R¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) is—OC(O)OR¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) is—OC(O)N(R¹¹)(R¹¹). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) is —SR¹¹. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is —S(O)R^(11a). In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(a) is —S(O)(NH)R¹¹. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(a) is —S(O)₂R^(11a). In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(a) is —S(O)₂N(R¹¹)(R¹¹). In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, one or more R^(a) is—N═S(R^(11a))(R^(11a))═O.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(a) is C₂₋₆ alkenyl, wherein the C₂₋₆alkenyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(a) is C₂₋₆ alkynyl, wherein the C₂₋₆alkynyl is optionally substituted with 1-3 R^(c) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is C₃₋₇ monocycliccycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl is optionallysubstituted with 1-3 R^(d) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(a) is C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀ fusedbicyclic cycloalkyl is optionally substituted with 1-3 R^(d) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is C₅₋₁₀ bridged bicycliccycloalkyl, wherein the C₅₋₁₀ bridged bicyclic cycloalkyl is optionallysubstituted with 1-3 R^(d) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(a) is phenyl, wherein the phenyl is optionally substituted with 1-3R^(d) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) isnaphthalenyl, wherein the naphthalenyl is optionally substituted with1-3 R^(d) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(a) is 4-7membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is optionally substituted with 1-3 R^(d) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(a) is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith 1-3 R^(d) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(a) is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is optionally substituted with 1-3 R^(d) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(a) is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-3 R^(d) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(a) is 8-10 membered fused bicyclicheteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl isoptionally substituted with 1-3 R^(d) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(a) is 7-10 membered spirocyclic heterocyclyl, wherein the7-10 membered spirocyclic heterocyclyl is optionally substituted with1-3 R^(d) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(b) independently is oxo, imino,halogen, —NO₂, —N₃, —CN, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fusedbicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 memberedmonocyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10membered bridged bicyclic heterocyclyl, 8-10 membered fused bicyclicheteroaryl, 7-10 membered spirocyclic heterocyclyl, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —C(O)N(R¹¹)(R¹¹), —NR¹¹R¹¹, —N(R¹¹)₂(R¹¹)⁺, —N(R¹¹)C(O)R¹¹,—N(R¹¹)C(O)OR¹¹, —N(R¹¹)C(O)N(R¹¹)(R¹¹), —N(R¹¹)S(O)₂(R^(11a)),—NR¹¹S(O)₂N(R¹¹)(R¹¹), —NR¹¹S(O)₂O(R^(11a)), —OC(O)R¹¹, —OC(O)OR¹¹,—OC(O)N(R¹¹)(R¹¹), —SR¹¹, —S(O)R^(11a), —S(O)(NH)R¹¹, —S(O)₂R^(11a),—S(O)₂N(R¹¹)(R¹¹), or —N═S(R^(11a))(R^(11a))═O,

-   -   wherein the C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic        cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,        naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 membered        monocyclic heteroaryl, 8-10 membered fused bicyclic        heterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10        membered fused bicyclic heteroaryl, and 7-10 membered        spirocyclic heterocyclyl are each independently optionally        substituted with 1-3 R^(d) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(b) independently is —OH, halogen, —CN,oxo, —NR¹¹R¹¹, C₁₋₄ alkoxy, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fusedbicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 memberedmonocyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 8-10membered bridged bicyclic heterocyclyl, 6-10 membered bridged bicyclicheterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10 memberedspirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(b) independently is —OH, halogen, —CN,oxo, —NR¹¹R¹¹, —C(O)N(R¹¹)(R¹¹), C₁₋₄ alkoxy, or 4-7 membered monocyclicheterocyclyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, each R^(b) independently is—OH, halogen, —CN, oxo, —NR¹¹R¹¹, or C₁₋₄ alkoxy. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,each R^(b) independently is —OH, halogen, —CN, oxo, —NR¹¹R¹¹, or C₁₋₃alkoxy. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, each R^(b) independently ishalogen or C₁₋₃ alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(b) independently is 4-7 memberedmonocyclic heterocyclyl, 8-10 membered fused bicyclic heterocyclyl, or6-10 membered bridged bicyclic heterocyclyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(b) is 4-7 membered monocyclic heterocyclyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(b) is 5-7 membered monocyclic heterocyclyl.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is 8-10 membered fusedbicyclic heterocyclyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(b) is 6-10membered bridged bicyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is oxo. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(b) is imino. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, one or moreR^(b) is halogen. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) is —NO₂. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is —N₃. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(b) is —CN. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(b) is —OR¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) is —C(O)R¹¹.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is —C(O)OR¹¹. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(b) is —C(O)N(R¹¹)(R¹¹). In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(b) is —NR¹¹R¹¹. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(b) is —N(R¹¹)₂(R¹¹). In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(b) is —N(R¹¹)C(O)R¹¹. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(b) is—N(R¹¹)C(O)OR¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) is—N(R¹¹)C(O)N(R¹)(R¹¹). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(b) is—N(R¹¹)S(O)₂(R^(11a)). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(b) is—NR¹¹S(O)₂N(R¹¹)(R¹¹). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(b) is—NR¹¹S(O)₂O(R^(11a)). In some embodiments of a compound of Formula I, ora pharmaceutically acceptable salt thereof, one or more R^(b) is—OC(O)R¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) is—OC(O)OR¹¹. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) is—OC(O)N(R¹¹)(R¹¹). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) is —SR¹¹. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is —S(O)R^(11a). In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(b) is —S(O)(NH)R¹¹. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(b) is —S(O)₂R^(11a). In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(b) is —S(O)₂N(R¹¹)(R¹¹). In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, one or more R^(b) is—N═S(R^(11a))(R^(11a))═O.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is C₃₋₇ monocycliccycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl is optionallysubstituted with 1-3 R^(d) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(b) is C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀ fusedbicyclic cycloalkyl is optionally substituted with 1-3 R^(d) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is C₅₋₁₀ bridged bicycliccycloalkyl, wherein the C₅₋₁₀ bridged bicyclic cycloalkyl is optionallysubstituted with 1-3 R^(d) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(b) is phenyl, wherein the phenyl is optionally substituted with 1-3R^(d) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) isnaphthalenyl, wherein the naphthalenyl is optionally substituted with1-3 R^(d) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(b) is 4-7membered monocyclic heterocyclyl, wherein the 4-7 membered monocyclicheterocyclyl is optionally substituted with 1-3 R^(d) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(b) is 5-6 membered monocyclic heteroaryl,wherein the 5-6 membered monocyclic heteroaryl is optionally substitutedwith 1-3 R^(d) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(b) is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is optionally substituted with 1-3 R^(d) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(b) is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-3 R^(d) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(b) is 8-10 membered fused bicyclicheteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl isoptionally substituted with 1-3 R^(d) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(b) is 7-10 membered spirocyclic heterocyclyl, wherein the7-10 membered spirocyclic heterocyclyl is optionally substituted with1-3 R^(d) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(c) independently is halogen, —CN, C₇₋₁₀fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl,naphthalenyl, 4-7 membered monocyclic heterocyclyl, 5-6 memberedmonocyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, 6-10membered bridged bicyclic heterocyclyl, 8-10 membered fused bicyclicheteroaryl, 7-10 membered spirocyclic heterocyclyl, —OR¹², —C(O)R¹²,—C(O)OR¹², —C(O)N(R¹²)(R¹²), —NR¹²R¹², —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)R¹²,—N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R^(12a)),—NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)), —OC(O)R¹², —OC(O)OR¹²,—OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a), —S(O)(NH)R¹², —S(O)₂R^(12a),—S(O)₂N(R¹²)(R¹²), or —N═S(R^(12a))(R^(12a))═O.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(c) is halogen. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(c) is —CN. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(c) is C₇₋₁₀ fused bicyclic cycloalkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(c) is C₅₋₁₀ bridged bicyclic cycloalkyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(c) is phenyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(c) is naphthalenyl. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(c) is 4-7 membered monocyclic heterocyclyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(c) is 5-6 membered monocyclic heteroaryl.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(c) is 8-10 membered fusedbicyclic heterocyclyl. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(c) is 6-10membered bridged bicyclic heterocyclyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(c) is 8-10 membered fused bicyclic heteroaryl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(c) is 7-10 membered spirocyclicheterocyclyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is —OR¹². Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(c) is —C(O)R¹². In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(c) is —C(O)OR¹². In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(c) is —C(O)N(R¹²)(R¹²). In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, one or moreR^(c) is —NR¹²R¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is—N(R¹²)₂(R¹²)⁺. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is—N(R¹²)C(O)R¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is—N(R¹²)C(O)OR¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is—N(R¹²)C(O)N(R¹²)(R¹²). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(c) is—N(R¹²)S(O)₂(R^(12a)). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(c) is—NR¹²S(O)₂N(R¹²)(R¹²). In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R^(c) is—NR¹²S(O)₂O(R^(12a)). In some embodiments of a compound of Formula I, ora pharmaceutically acceptable salt thereof, one or more R^(c) is—OC(O)R¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is—OC(O)OR¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is—OC(O)N(R¹²)(R¹²). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(c) is —SR¹². Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(c) is —S(O)R^(12a). In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(c) is —S(O)(NH)R¹². In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(c) is —S(O)₂R^(12a). In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(c) is —S(O)₂N(R¹²)(R¹²). In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, one or more R^(c) is—N═S(R^(12a))(R^(12a))═O.

In some embodiments of a compound of Formula I or II, or apharmaceutically acceptable salt thereof, each R^(c) independently is—OH, halogen, —CN, oxo, or —NR¹²R¹². In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, each R^(c)independently is —OH, halogen, —CN, or —NR¹²R¹². In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(c) is —OH. In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, one or more R^(c) ishalogen.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(d) independently is oxo, halogen, —CN,C₁₋₆ alkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀ bridged bicycliccycloalkyl, phenyl, naphthalenyl, 4-7 membered monocyclic heterocyclyl,5-6 membered monocyclic heteroaryl, 8-10 membered fused bicyclicheterocyclyl, 6-10 membered bridged bicyclic heterocyclyl, 8-10 memberedfused bicyclic heteroaryl, 7-10 membered spirocyclic heterocyclyl,—OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)(R¹²), —NR¹²R¹², —N(R¹²)₂(R¹²)⁺,—N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹²),—N(R¹²)S(O)₂(R^(12a)), —NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R^(12a)),—OC(O)R¹², —OC(O)OR¹², —OC(O)N(R¹²)(R¹²), —SR¹², —S(O)R^(12a),—S(O)(NH)R¹², —S(O)₂R^(12a), —S(O)₂N(R¹²)(R¹²) or—N═S(R^(12a))(R^(12a))═O,

-   -   wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH, halogen, —CN, and C₁₋₃ alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(d) is oxo. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(d) is halogen. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, one or moreR^(d) is —CN. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) is C₇₋₁₀fused bicyclic cycloalkyl. In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, one or more R^(d) isC₅₋₁₀ bridged bicyclic cycloalkyl. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(d) is phenyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) isnaphthalenyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) is 4-7membered monocyclic heterocyclyl. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(d) is 5-6 membered monocyclic heteroaryl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is 8-10 membered fused bicyclic heterocyclyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(d) is 6-10 membered bridged bicyclicheterocyclyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) is 8-10membered fused bicyclic heteroaryl. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(d) is 7-10 membered spirocyclic heterocyclyl. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is —OR¹². In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, one or more R^(d) is—C(O)R¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) is—C(O)OR¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) is—C(O)N(R¹²)(R¹²). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) is —NR¹²R¹².In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(d) is —N(R¹²)₂(R¹²)⁺. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(d) is —N(R¹²)C(O)R¹². In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(d) is —N(R¹²)C(O)OR¹². In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is —N(R¹²)C(O)N(R¹²)(R¹²). In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is —N(R¹²)S(O)₂(R^(12a)). In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is —NR¹²S(O)₂N(R¹²)(R¹²). In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is —NR¹²S(O)₂O(R^(12a)). In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is —OC(O)R¹². In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(d) is —OC(O)OR¹². In some embodiments of a compound of Formula I, ora pharmaceutically acceptable salt thereof, one or more R^(d) is—OC(O)N(R¹²)(R¹²). In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(d) is —SR¹². Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(d) is —S(O)R^(12a). In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(d) is —S(O)(NH)R¹². In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(d) is —S(O)₂R^(12a). In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR^(d) is —S(O)₂N(R¹²)(R¹²). In some embodiments of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, one or more R^(d) is—N═S(R^(12a))(R^(12a))═O.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(d) is C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,—CN, and C₁₋₃ alkoxy.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹¹ independently is H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10membered spirocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇        monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀        bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7 membered        monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,        8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        and 7-10 membered spirocyclic heterocyclyl are each        independently optionally substituted with 1-3 R^(c) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹¹ independently is H, C₁₋₆ alkyl, C₃₋₇monocyclic cycloalkyl, or 4-7 membered monocyclic heterocyclyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, each R¹¹ independently is H or C₁₋₄ alkyl, wherein theC₁₋₄ alkyl is optionally substituted with one group selected from —OHand —NR¹²R¹². In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, each R¹¹ independently is H orC₁₋₄ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, each R¹¹ independently is H orC₁₋₃ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, each R¹¹ independently is H ormethyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹¹ independently is H or C₁₋₆ alkyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹¹ independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹¹ of —NR¹¹R¹¹ and —C(O)NR¹¹R¹¹independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R¹¹ is C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R¹¹ is C₁₋₄ alkyl, wherein the C₁₋₄ alkyl isoptionally substituted with 1-3 R^(c) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹¹ is methyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R¹¹ is H. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹¹ is C₂₋₆ alkenyl, wherein the C₂₋₆ alkenyl is optionallysubstituted with 1-3 R^(c) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR¹¹ is C₂₋₆ alkynyl, wherein the C₂₋₆ alkynyl is optionally substitutedwith 1-3 R^(c) groups. In some embodiments of a compound of Formula I,or a pharmaceutically acceptable salt thereof, one or more R¹¹ is C₃₋₇monocyclic cycloalkyl, wherein the C₃₋₇ monocyclic cycloalkyl isoptionally substituted with 1-3 R^(c) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹¹ is C₇₋₁₀ fused bicyclic cycloalkyl, wherein the C₇₋₁₀fused bicyclic cycloalkyl is optionally substituted with 1-3 R^(c)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R¹¹ is C₅₋₁₀bridged bicyclic cycloalkyl, wherein the C₅₋₁₀ bridged bicycliccycloalkyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R¹¹ is phenyl, wherein the phenyl isoptionally substituted with 1-3 R^(c) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹¹ is naphthalenyl, wherein the naphthalenyl is optionallysubstituted with 1-3 R^(c) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR¹¹ is 4-7 membered monocyclic heterocyclyl, wherein the 4-7 memberedmonocyclic heterocyclyl is optionally substituted with 1-3 R^(c) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R¹¹ is 5-6 membered monocyclicheteroaryl, wherein the 5-6 membered monocyclic heteroaryl is optionallysubstituted with 1-3 R^(c) groups. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR¹¹ is 8-10 membered fused bicyclic heterocyclyl, wherein the 8-10membered fused bicyclic heterocyclyl is optionally substituted with 1-3R^(c) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R¹¹ is 6-10membered bridged bicyclic heterocyclyl, wherein the 6-10 memberedbridged bicyclic heterocyclyl is optionally substituted with 1-3 R^(c)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R¹¹ is 8-10membered fused bicyclic heteroaryl, wherein the 8-10 membered fusedbicyclic heteroaryl is optionally substituted with 1-3 R^(c) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R¹¹ is 7-10 membered spirocyclicheterocyclyl, wherein the 7-10 membered spirocyclic heterocyclyl isoptionally substituted with 1-3 R^(c) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R^(11a) independently is C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10membered spirocyclic heterocyclyl,

-   -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇        monocyclic cycloalkyl, C₇₋₁₀ fused bicyclic cycloalkyl, C₅₋₁₀        bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7 membered        monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,        8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridged        bicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl,        and 7-10 membered spirocyclic heterocyclyl are each        independently optionally substituted with 1-3 R^(c) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(11a) is C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(11a) is C₂₋₆ alkenyl, wherein the C₂₋₆alkenyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(11a) is C₂₋₆ alkynyl, wherein the C₂₋₆alkynyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(11a) is C₃₋₇ monocyclic cycloalkyl, whereinthe C₃₋₇ monocyclic cycloalkyl is optionally substituted with 1-3 R^(c)groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(11a) is C₇₋₁₀fused bicyclic cycloalkyl, wherein the C₇₋₁₀ fused bicyclic cycloalkylis optionally substituted with 1-3 R^(c) groups. In some embodiments ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(11a) is C₅₋₁₀ bridged bicyclic cycloalkyl, wherein theC₅₋₁₀ bridged bicyclic cycloalkyl is optionally substituted with 1-3R^(c) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(11a) is phenyl,wherein the phenyl is optionally substituted with 1-3 R^(c) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(11a) is naphthalenyl, whereinthe naphthalenyl is optionally substituted with 1-3 R^(c) groups. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(11a) is 4-7 membered monocyclicheterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-3 R^(c) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(11a) is 5-6 membered monocyclic heteroaryl, wherein the5-6 membered monocyclic heteroaryl is optionally substituted with 1-3R^(c) groups. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(11a) is 8-10membered fused bicyclic heterocyclyl, wherein the 8-10 membered fusedbicyclic heterocyclyl is optionally substituted with 1-3 R^(c) groups.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(11a) is 6-10 membered bridgedbicyclic heterocyclyl, wherein the 6-10 membered bridged bicyclicheterocyclyl is optionally substituted with 1-3 R^(c) groups. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(11a) is 8-10 membered fused bicyclicheteroaryl, wherein the 8-10 membered fused bicyclic heteroaryl isoptionally substituted with 1-3 R^(c) groups. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(11a) is 7-10 membered spirocyclic heterocyclyl, whereinthe 7-10 membered spirocyclic heterocyclyl is optionally substitutedwith 1-3 R^(c) groups.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹² independently is H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹² independently is H or C₁₋₄ alkyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹² independently is H or C₁₋₃ alkyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R¹² is H. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹² is C₁₋₆ alkyl. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR¹² is C₁₋₄ alkyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R¹² is C₁₋₃ alkyl.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R¹² is C₂₋₆ alkenyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R¹² is C₂₋₆ alkynyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹² is C₃₋₇ monocyclic cycloalkyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹² is C₇₋₁₀ fused bicyclic cycloalkyl. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R¹² is C₅₋₁₀ bridged bicyclic cycloalkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R¹² is phenyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹² is naphthalenyl. In some embodiments of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, one or moreR¹² is 4-7 membered monocyclic heterocyclyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹² is 5-6 membered monocyclic heteroaryl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R¹² is 8-10 membered fused bicyclicheterocyclyl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R¹² is 6-10membered bridged bicyclic heterocyclyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R¹² is 8-10 membered fused bicyclic heteroaryl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R¹² is 7-10 membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, each R¹², independently is C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ monocyclic cycloalkyl, C₇₋₁₀ fused bicycliccycloalkyl, C₅₋₁₀ bridged bicyclic cycloalkyl, phenyl, naphthalenyl, 4-7membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl,8-10 membered fused bicyclic heterocyclyl, 6-10 membered bridgedbicyclic heterocyclyl, 8-10 membered fused bicyclic heteroaryl, or 7-10membered spirocyclic heterocyclyl.

In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(12a) is C₁₋₆ alkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(12a) is C₂₋₆ alkenyl. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(12a) is C₂₋₆ alkynyl. In some embodiments of acompound of Formula I, or a pharmaceutically acceptable salt thereof,one or more R^(12a) is C₃₋₇ monocyclic cycloalkyl. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(12a) is C₇₋₁₀ fused bicyclic cycloalkyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(12a) is C₅₋₁₀ bridged bicyclic cycloalkyl.In some embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(12a) is phenyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(12a) is naphthalenyl. In some embodimentsof a compound of Formula I, or a pharmaceutically acceptable saltthereof, one or more R^(12a) is 4-7 membered monocyclic heterocyclyl. Insome embodiments of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, one or more R^(12a) is 5-6 membered monocyclicheteroaryl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(12a) is 8-10membered fused bicyclic heterocyclyl. In some embodiments of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, one or moreR^(12a) is 6-10 membered bridged bicyclic heterocyclyl. In someembodiments of a compound of Formula I, or a pharmaceutically acceptablesalt thereof, one or more R^(12a) is 8-10 membered fused bicyclicheteroaryl. In some embodiments of a compound of Formula I, or apharmaceutically acceptable salt thereof, one or more R^(12a) is 7-10membered spirocyclic heterocyclyl.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

III. Compositions and Kits

Compounds provided herein, or pharmaceutically acceptable salts thereof,are usually administered in the form of pharmaceutical compositions.Thus, provided herein are also pharmaceutical compositions that compriseone or more of the compounds provided herein or pharmaceuticallyacceptable salts, isomer, or a mixture thereof and one or morepharmaceutically acceptable vehicles selected from carriers, adjuvantsand excipients. The compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be the sole active ingredient or one ofthe active ingredients of the pharmaceutical compositions. Suitablepharmaceutically acceptable vehicles may include, for example, inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants. Such compositions are prepared in a manner well known in thepharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, MacePublishing Co., Philadelphia, Pa. 17th Ed. (1985); and ModemPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes,Eds.).

In one embodiment, provided herein are pharmaceutical compositionscomprising a compound provided herein (i.e., a compound of Formula I),or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier. In some embodiments, the pharmaceuticalcompositions comprise a therapeutically effective amount of a compoundprovided herein, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (i.e., one, two, three, four; one or two;one to three; or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (i.e., one, two, three, four; one or two; oneto three; or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agentscomprises an anti-malarial agent. In some embodiments, the anti-malarialagent is selected from chloroquine and hydroxychloroquine, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for an inflammatory condition. Insome embodiments, the one or more additional therapeutic agents isselected from the group consisting of: veltuzumab, PF-06835375,eculizumab, milatuzumab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721,AK-101, TNX-1500, theralizumab, daxdilimab, TAK-079, felzartamab,itolizumab, anifrolumab, iscalimab, dapirolizumab pegol, lanalumab,LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059,obexelimab, talacotuzumab, vobarilizumab, TE-2324, PRV-3279,chloroquine, hydroxychloroquine, hydroxychloroquine sulfate,COV-08-0064; GNKS-356, AVO-101, rozibafusp alfa, VRN-02, annexuzlimab,ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, atacicept,telitacicept, BMS-986256, M-5049, KZR-616, KPG-818, verdinexor,ALPN-303, valziflocept, LA-1, cenerimod, prednisone, corticotropin,deucravacitinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830,DV-1079, julemic acid, iberdomide, TAM-01, BML-258, brepocitinib,SDC-1801, SDC-1802, ICP-330, NTR-441, dalazatide, GSK-2646264,SKI-O-703, lanraplenib (GS-9876), GNS-1653, HMPL-523, RSLV-132,interleukin-2 follow-on biologic, interleukin-2 Anteluke, interkingrecombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylatedHLA-x (SLE), AC-0058, fenebrutinib, XNW-1011, tirabrutinibhydrochloride, branebrutinib, elsubrutinib, orelabrutinib, DWP-213388,INV-103, R-salbutamol sulphate, anchorins, NIK-SMI1, X-6, INV-17, OshadiD, baricitinib, upadacitinib, filgotinib, itacitinib, INCB-54707,delgocitinib, DWP-212525, CKD-971, as mometasone, betamethasone,forigerimod, anandamide, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710(edratide), allogeneic human umbilical cord-derived mesenchymal stemcell therapy (hUC-MSCs), LC-200, BI-705564, SM-934, GX-101, TXR-712,TXR-711, CIT-013, MHV-370, Panzyga®, TPX-6001, TPX-7001, artenimol, andAMG-592, or a pharmaceutically acceptable salt of any of the foregoing,or any combinations thereof.

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical compositions may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In some embodiments, the pharmaceutical compositionsmay be administered by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles. Insome embodiments, the compounds, or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions disclosed herein areadministered by subcutaneous injection.

The pharmaceutical compositions of the present disclosure may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned herein. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

In some embodiments, the sterile injectable preparation disclosed hereinmay also be a sterile injectable solution or suspension prepared from areconstituted lyophilized powder in a non-toxic parenterally acceptablediluent or solvent, such as a solution in 1,3-butane-diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile fixed oils may conventionally be employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid may likewise be used in the preparation of injectables.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. In certain embodiments the suspension is a microsuspension. Incertain embodiments the suspension is a nanosuspension.

In some embodiments, formulations suitable for parenteral administration(e.g., intramuscular (IM) and subcutaneous (SC) administration) willinclude one or more excipients. Excipients should be compatible with theother ingredients of the formulation and physiologically innocuous tothe recipient thereof. Examples of suitable excipients are well known tothe person skilled in the art of parenteral formulation and may be founde.g., in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey &Quinn), 6th edition 2009. Examples of solubilizing excipients in aparenteral formulation (e.g., an SC or IM formulation) include, but arenot limited to, polysorbates (such as polysorbate 20 or 80) andpoloxamers (such as poloxamer 338, 188, or 207).

In some embodiments, the compounds, or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions disclosed herein areadministered with implants.

Oral administration may be another route for administration of thecompounds provided herein or pharmaceutically acceptable salts thereof.Administration may be via, for example, capsule or enteric coatedtablets. In making the pharmaceutical compositions that include at leastone compound provided herein or pharmaceutically acceptable salts,isomer, or a mixture thereof, the active ingredient (such as a compoundprovided herein) is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material, which acts asa vehicle, carrier or medium for the active ingredient. Thus, thepharmaceutical compositions can be in the form of tablets, pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium),ointments containing, for example, up to 10% by weight of the activecompound, soft and hard gelatin capsules, sterile injectable solutions,and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose or any combinations thereof. The pharmaceutical compositionscan additionally include lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl and propylhydroxy-benzoates;sweetening agents; and flavoring agents; or any combinations thereof.

The pharmaceutical compositions that include at least one compounddescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof can be formulated so as to provide quick, sustained ordelayed release of the active ingredient (such as a compound providedherein) after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolutional systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations. Examples of controlled release systems are given in U.S.Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Anotherformulation for use in the methods of the present disclosure employstransdermal delivery devices (“patches”). Such transdermal patches maybe used to provide continuous or discontinuous infusion of the compoundsprovided herein in controlled amounts. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and5,001,139. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof. When referring to these preformulationcompositions as homogeneous, the active ingredient may be dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

The tablets or pills of the compounds provided herein orpharmaceutically acceptable salts thereof may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with materials such as shellac, cetyl alcohol, andcellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described supra. In some embodiments, the compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. In other embodiments, compositions in pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be inhaled directly from the nebulizing device or thenebulizing device may be attached to a facemask tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

In one embodiment, provided herein are kits that comprise a compoundprovided herein, (i.e., a compound of Formula I), or a pharmaceuticallyacceptable salt, stereoisomer, prodrug, or solvate thereof, and suitablepackaging. In some embodiments, the kit further comprises instructionsfor use. In some embodiments, the kit comprises a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt, stereoisomer, prodrug, or solvate thereof, and a label and/orinstructions for use of the compounds in the treatment of theindications, including the diseases or conditions, described herein.

In some embodiments, the kits further comprise one or more (i.e., one,two, three, four; one or two; one to three; or one to four) additionaltherapeutic agents, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein are articles of manufacture thatcomprise a compound described herein or pharmaceutically acceptablesalts, isomer, or a mixture thereof in a suitable container. In someembodiments, the container may be a vial, jar, ampoule, preloadedsyringe, or intravenous bag.

IV. Methods

The methods provided herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods provided herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the present disclosure maybe used for a variety of purposes, including therapeutic andexperimental purposes. For example, the present disclosure may be usedex vivo to determine the optimal schedule and/or dosing ofadministration of a TLR 7, 8, and/or 9 inhibitor as disclosed herein fora given cell type, individual, and other parameters. Information gleanedfrom such use may be used for experimental purposes or in the clinic toset protocols for in vivo treatment. Other ex vivo uses for which thepresent disclosure may be suited are described below or will becomeapparent to those skilled in the art. The selected compounds may befurther characterized to examine the safety or tolerance dosage in humanor non-human subjects. Such properties may be examined using commonlyknown methods to those skilled in the art.

In one embodiment, the present disclosure provides a method ofinhibiting toll-like receptor 7, 8, and/or 9 activity in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the present disclosure provides amethod of inhibiting toll-like receptor 7, 8, and 9 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the present disclosure provides amethod of inhibiting toll-like receptor 7, 8, or 9 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a method ofinhibiting toll-like receptor 7 and/or 8 activity in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the present disclosure provides amethod of inhibiting toll-like receptor 7 and 8 activity in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the present disclosure provides amethod of inhibiting toll-like receptor 7 or 8 activity in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a method ofinhibiting toll-like receptor 7 activity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (i.e., a compound of Formula I), ora pharmaceutically acceptable salt thereof, or a therapeuticallyeffective amount of a pharmaceutical composition provided herein. Insome embodiments, the present disclosure provides a method of inhibitingtoll-like receptor 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (i.e., a compound of Formula I), or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein.

In one embodiment, the present disclosure provides a method of treatinga disease or disorder associated with elevated toll-like receptor 7, 8,and/or 9 activity in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a therapeutically effective amount of a pharmaceuticalcomposition provided herein. In some embodiments, the present disclosureprovides a method of treating a disease or disorder associated withelevated toll-like receptor 7, 8, and 9 activity in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the present disclosure provides amethod of treating a disease or disorder associated with elevatedtoll-like receptor 7, 8, or 9 activity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (i.e., a compound of Formula I), ora pharmaceutically acceptable salt thereof, or a therapeuticallyeffective amount of a pharmaceutical composition provided herein.

In one embodiment, the present disclosure provides a method of treatinga disease or disorder associated with elevated toll-like receptor 7and/or 8 activity in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a therapeutically effective amount of a pharmaceuticalcomposition provided herein. In some embodiments, the present disclosureprovides a method of treating a disease or disorder associated withelevated toll-like receptor 7 and 8 activity in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the present disclosure provides amethod of treating a disease or disorder associated with elevatedtoll-like receptor 7 or 8 activity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (i.e., a compound of Formula I), ora pharmaceutically acceptable salt thereof, or a therapeuticallyeffective amount of a pharmaceutical composition provided herein.

In one embodiment, the present disclosure provides a method of treatinga disease or disorder associated with elevated toll-like receptor 7activity in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound provided herein(i.e., a compound of Formula I), or a pharmaceutically acceptable saltthereof, or a therapeutically effective amount of a pharmaceuticalcomposition provided herein. In some embodiments, the present disclosureprovides a method of treating a disease or disorder associated withelevated toll-like receptor 8 activity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (i.e., a compound of Formula I), ora pharmaceutically acceptable salt thereof, or a therapeuticallyeffective amount of a pharmaceutical composition provided herein.

In one embodiment, the present disclosure provides a method of treatingan inflammatory condition in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (i.e., a compound of Formula I), or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein.

Non-limiting examples of an inflammatory condition include, withoutlimitation, acne, acid-induced lung injury, Addison's disease, adrenalhyperplasia, adrenocortical insufficiency, adult-onset Still's disease,adult respiratory distress syndrome (ARDS), age-related maculardegeneration, aging, alcoholic hepatitis, alcoholic liver disease,allergen-induced asthma, allergic bronchopulmonary, allergicconjunctivitis, allergic contact dermatitis, allergies, allergicencephalomyelitis, allergic neuritis, allograft rejection, alopecia,alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateralsclerosis, angina pectoris, angioedema, angiofibroma, anhidroticectodermal dysplasia-ill, anti-glomerular basement membrane disease,antigen-antibody complex mediated diseases, ankylosing spondylitis,antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis,ascites, aspergillosis, asthma, atherosclerosis, atheroscleroticplaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases,autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnalhemoglobinuria), autoimmune polyendocrinopathies, autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders,autoinflammatory diseases, back pain, Bacillus anthracis infection,Bechet's disease, bee sting-induced inflammation, Behget's syndrome,Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis,bullous pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy,carpal tunnel syndrome, Castleman's disease, catabolic disorders,cataracts, Celiac disease, cerebral aneurysm, chemical irritant-inducedinflammation, chorioretinitis, chronic atypical neutrophilic dermatosiswith lipodystrophy and elevated temperature (CANDLE) syndrome, chronicheart failure, chronic lung disease of prematurity, chronic obstructivepulmonary disease (COPD), chronic pancreatitis, chronic prostatitis,chronic recurrent multifocal osteomyelitis, cicatricial alopecia,colitis, complex regional pain syndrome, complications of organtransplantation, conjunctivitis, connective tissue disease, contactdermatitis, corneal graft neovascularization, corneal ulcer, Crohn'sdisease, cryopyrin-associated periodic syndromes, cutaneous lupuserythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of theinterleukin-1 receptor antagonist (DIRA), dermatitis, dermatitisendotoxemia, dermatomyositis, diabetic macular edema, diverticulitis,eczema, encephalitis, endometriosis, endotoxemia, eosinophilicpneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme,erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy,familial cold urticarial, familial Mediterranean fever, fetal growthretardation, fibromyalgia, fistulizing Crohn's disease, food allergies,giant cell arteritis, glaucoma, glioblastoma, glomerular disease,glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy,gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatoushepatitis, Graves' disease, growth plate injuries, Guillain-Barresyndrome. gut diseases, hair loss, Hashimoto's thyroiditis, head injury,headache, hearing loss, heart disease, hemangioma, hemolytic anemia,hemophilic joints, Henoch-Scholein purpura, hepatitis, hereditaryperiodic fever syndrome, heritable disorders of connective tissue,herpes zoster and simplex, hidradenitis suppurativa (HS), hipreplacement, Hodgkin's disease, Huntington's disease, hyaline membranedisease, hyperactive inflammatory response, hyperammonemia,hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES),hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivitypneumonitis, hypertropic bone formation, hypoplastic and other anemias,hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy,Idiopathic inflammatory myopathies (dermatomyositis, polymyositis),idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura,immunoglobulin nephropathies, immune complex nephritis, immunethrombocytopenic purpura (ITP), incontinentia pigmenti (IP,Bloch-Siemens syndrome), infectious mononucleosis, infectious diseasesincluding viral diseases such as AIDS (HIV infection), hepatitis A, B,C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatorybowel disease (IBD), inflammatory disease of the lower respiratory tractincluding bronchitis or chronic obstructive pulmonary diseases,inflammatory disease of the upper respiratory tract including the noseand sinuses such as rhinitis or sinusitis, inflammatory diseases of therespiratory tract, inflammatory ischemic event such as stroke or cardiacarrest, inflammatory lung disease, inflammatory myopathy such asmyocarditis, inflammatory liver disease, inflammatory neuropathy,inflammatory pain, insect bite-induced inflammation, interstitialcystitis, interstitial lung disease, iritis, irritant-inducedinflammation, ischemia/reperfusion, joint replacement, juvenilearthritis, juvenile rheumatoid arthritis, keratitis, kidney injurycaused by parasitic infections, kidney transplant rejection,leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS),Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupusnephritis, Lyme disease, Marfan syndrome (MFS), mast cell activationsyndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixedconnective tissue disease, Muckle-Wells syndrome (urticaria deafnessamyloidosis), mucositis, multiple organ injury syndrome, multiplesclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG),myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis,necrotizing enterocolitis, neonatal onset multisystem inflammatorydisease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis,neuropathological diseases, non-allergen induced asthma, obesity, ocularallergy, optic neuritis, organ transplant rejection, Osier-Webersyndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis,osteoporosis, osterarthritis, otitis, pachyonychia congenita, Paget'sdisease, Paget's disease of bone, pancreatitis, Parkinson's disease,pediatric rheumatology, pelvic inflammatory disease, pemphigus,pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodicfever, periodontitis, peritoneal endometriosis, pernicious anemia(Addison's disease), pertussis, PFAPA (periodic fever aphthouspharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPAsyndrome), plant irritant-induced inflammation, pneumocystis infection,pneumonia, pneumonitis, poison ivy/urushiol oil-induced inflammation,polyarthritis nodosa, polychondritis, polycystic kidney disease,polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis,reperfusion injury and transplant rejection, primary biliary cirrhosis,primary pulmonary hypertension, primary sclerosing cholangitis (PSC),proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriaticepidermis, psychosocial stress diseases, pulmonary disease, pulmonaryfibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenicgranuloma retrolental fibroplasias, pyogenic sterile arthritis,Raynaud's syndrome, Reiter's disease, reactive arthritis, renal disease,renal graft rejection, reperfusion injury, respiratory distresssyndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome,rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoidarthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis,Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis,seborrhea, sepsis, septic shock, severe pain, Sézary syndrome, sicklecell anemia, silica-induced disease (Silicosis), Sjogren's syndrome,skin diseases, skin irritation, skin rash, skin sensitization (contactdermatitis or allergic contact dermatitis), sleep apnea, spinal cordinjury, spinal stenosis, spondyloarthropathies, sports injuries, sprainsand strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoidhemorrhage, sunburn, synovial inflammation, systemic inflammatoryresponse syndrome (SIRS), systemic lupus erythematosus (SLE), systemicmast cell disease (SMCD), systemic vasculitis, systemic-onset juvenileidiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis,thrombocytopenia, thyroditis, thyroiditis, tissue transplant,toxoplasmosis, trachoma, transplantation rejection, traumatic braininjury, tuberculosis, tubulointerstitial nephritis, tumor necrosisfactor (TNF) receptor associated periodic syndrome (TRAPS), type 1diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes,ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis,vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener'sgranulomatosis, and Whipple's disease.

In some embodiments, the inflammatory condition is selected frominflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoidarthritis, glomerulonephritis, mixed connective tissue disease (MCTD),dermatomyositis, polymyositis, systemic sclerosis, antineutrophilcytoplasmic antibody-associated vasculitis, anti-phospholipid syndrome,autoimmune hemolytic anemia, macrophage activation syndrome driveninflammatory anemia, IgA nephropathy, type I diabetes, non-alcoholicsteatohepatitis, and Sjogren's syndrome. In some embodiments, theinflammatory condition is inflammatory bowel disease. In someembodiments, the inflammatory condition is psoriasis. In someembodiments, the inflammatory condition is psoriatic arthritis. In someembodiments, the inflammatory condition is rheumatoid arthritis. In someembodiments, the inflammatory condition is glomerulonephritis. In someembodiments, the inflammatory condition is mixed connective tissuedisease (MCTD). In some embodiments, the inflammatory condition isdermatomyositis. In some embodiments, the inflammatory condition ispolymyositis. In some embodiments, the inflammatory condition issystemic sclerosis. In some embodiments, the inflammatory condition isantineutrophil cytoplasmic antibody-associated vasculitis. In someembodiments, the inflammatory condition is anti-phospholipid syndrome.In some embodiments, the inflammatory condition is autoimmune hemolyticanemia. In some embodiments, the inflammatory condition is macrophageactivation syndrome driven inflammatory anemia. In some embodiments, theinflammatory condition is IgA nephropathy. In some embodiments, theinflammatory condition is type I diabetes. In some embodiments, theinflammatory condition is non-alcoholic steatohepatitis. In someembodiments, the inflammatory condition is Sjogren's syndrome.

The compounds provided herein, or pharmaceutically acceptable saltsthereof, or the pharmaceutical composition provided herein may treat orameliorate systemic lupus erythematosus (SLE), cutaneous lupuserythematosus (CLE), lupus nephritis, lupus-related, symptom of SLE,symptom of CLE, or other autoimmune disorder. Symptoms of systemic lupuserythematosus include joint pain, joint swelling, arthritis, fatigue,hair loss, mouth sores, swollen lymph nodes, sensitivity to sunlight,skin rash, headaches, numbness, tingling, seizures, vision problems,personality changes, abdominal pain, nausea, vomiting, abnormal heartrhythms, coughing up blood and difficulty breathing, patchy skin colorand Raynaud's phenomenon.

In one embodiment, the present disclosure provides a method of treatingsystemic lupus erythematosus in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (i.e., a compound of Formula I), or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein.

In one embodiment, the present disclosure provides a method of treatingcutaneous lupus erythematosus in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (i.e., a compound of Formula I), or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein.

In one embodiment, the present disclosure provides a method of treatinglupus nephritis in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a therapeutically effective amount of a pharmaceuticalcomposition provided herein.

In some embodiments, the methods provided herein further compriseadministering a therapeutically effective amount of one or moreadditional therapeutic agents, or a pharmaceutically acceptable saltthereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of veltuzumab, PF-06835375,eculizumab, milatuzumab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721,AK-101, TNX-1500, theralizumab, daxdilimab, TAK-079, felzartamab,itolizumab, anifrolumab, iscalimab, dapirolizumab pegol, lanalumab,LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059,obexelimab, talacotuzumab, vobarilizumab, TE-2324, PRV-3279,chloroquine, hydroxychloroquine, hydroxychloroquine sulfate,COV-08-0064; GNKS-356, AVO-101, rozibafusp alfa, VRN-02, annexuzlimab,ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, atacicept,telitacicept, BMS-986256, M-5049, KZR-616, KPG-818, verdinexor,ALPN-303, valziflocept, LA-1, cenerimod, prednisone, corticotropin,deucravacitinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830,DV-1079, julemic acid, iberdomide, TAM-01, BML-258, brepocitinib,SDC-1801, SDC-1802, ICP-330, NTR-441, dalazatide, GSK-2646264,SKI-O-703, lanraplenib (GS-9876), GNS-1653, HMPL-523, RSLV-132,interleukin-2 follow-on biologic, interleukin-2 Anteluke, interkingrecombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylatedHLA-x (SLE), AC-0058, fenebrutinib, XNW-1011, tirabrutinibhydrochloride, branebrutinib, elsubrutinib, orelabrutinib, DWP-213388,INV-103, R-salbutamol sulphate, anchorins, NIK-SMI1, X-6, INV-17, OshadiD, baricitinib, upadacitinib, filgotinib, itacitinib, INCB-54707,delgocitinib, DWP-212525, CKD-971, as mometasone, betamethasone,forigerimod, anandamide, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710(edratide), allogeneic human umbilical cord-derived mesenchymal stemcell therapy (hUC-MSCs), LC-200, BI-705564, SM-934, GX-101, TXR-712,TXR-711, CIT-013, MHV-370, Panzyga®, TPX-6001, TPX-7001, artenimol, andAMG-592, or a pharmaceutically acceptable salt of any of the foregoing,or any combination thereof.

In some embodiments, the one or more additional therapeutic agents isselected from chloroquine and hydroxychloroquine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the one or more additionaltherapeutic agents is chloroquine. In some embodiments, the one or moreadditional therapeutic agents is hydroxychloroquine. In someembodiments, the one or more additional therapeutic agent is apharmaceutically acceptable salt of hydroxychloroquine. In someembodiments, the one or more additional therapeutic agent ishydroxychloroquine sulfate.

In some embodiments of the methods provided herein, the subject is ahuman.

In some embodiments, the methods provided herein comprise administeringa therapeutically effective amount of a compound provided herein (i.e.,a compound of Formula I), or a pharmaceutically acceptable salt thereof.In some embodiments, the methods provided herein comprise administeringa therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein for use intherapy.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of inhibiting toll-like receptor 7, 8, and/or 9 activity ina subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the compound provided herein(i.e., a compound of Formula I), or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition provided herein is for use ina method of inhibiting toll-like receptor 7, 8, and 9 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the compound provided herein(i.e., a compound of Formula I), or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition provided herein is for use ina method of inhibiting toll-like receptor 7, 8, or 9 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of inhibiting toll-like receptor 7 and/or 8 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the compound provided herein(i.e., a compound of Formula I), or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition provided herein is for use ina method of inhibiting toll-like receptor 7 and 8 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the compound provided herein(i.e., a compound of Formula I), or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition provided herein is for use ina method of inhibiting toll-like receptor 7 or 8 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of inhibiting toll-like receptor 7 activity in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein. In some embodiments, the compound provided herein(i.e., a compound of Formula I), or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition provided herein is for use ina method of inhibiting toll-like receptor 8 activity in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of treating a disease or disorder associated with elevatedtoll-like receptor 7, 8, and/or 9 activity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (i.e., a compound of Formula I), ora pharmaceutically acceptable salt thereof, or a therapeuticallyeffective amount of a pharmaceutical composition provided herein. Insome embodiments, the compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition provided herein is for use in a method oftreating a disease or disorder associated with elevated toll-likereceptor 7, 8, and 9 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (i.e., a compound of Formula I), or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein. In someembodiments, the compound provided herein (i.e., a compound of FormulaI), or a pharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition provided herein is for use in a method of treating a diseaseor disorder associated with elevated toll-like receptor 7, 8, or 9activity in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound provided herein(i.e., a compound of Formula I), or a pharmaceutically acceptable saltthereof, or a therapeutically effective amount of a pharmaceuticalcomposition provided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of treating a disease or disorder associated with elevatedtoll-like receptor 7 and/or 8 activity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (i.e., a compound of Formula I), ora pharmaceutically acceptable salt thereof, or a therapeuticallyeffective amount of a pharmaceutical composition provided herein. Insome embodiments, the compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition provided herein is for use in a method oftreating a disease or disorder associated with elevated toll-likereceptor 7 and 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (i.e., a compound of Formula I), or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein. In someembodiments, the compound provided herein (i.e., a compound of FormulaI), or a pharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition provided herein is for use in a method of treating a diseaseor disorder associated with elevated toll-like receptor 7 or 8 activityin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of treating a disease or disorder associated with elevatedtoll-like receptor 7 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein (i.e., a compound of Formula I), or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition provided herein. In someembodiments, the compound provided herein (i.e., a compound of FormulaI), or a pharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition provided herein is for use in a method of treating a diseaseor disorder associated with elevated toll-like receptor 8 activity in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof,or a therapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of treating an inflammatory condition in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein.

Non-limiting examples of an inflammatory condition include, withoutlimitation, acne, acid-induced lung injury, Addison's disease, adrenalhyperplasia, adrenocortical insufficiency, adult-onset Still's disease,adult respiratory distress syndrome (ARDS), age-related maculardegeneration, aging, alcoholic hepatitis, alcoholic liver disease,allergen-induced asthma, allergic bronchopulmonary, allergicconjunctivitis, allergic contact dermatitis, allergies, allergicencephalomyelitis, allergic neuritis, allograft rejection, alopecia,alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateralsclerosis, angina pectoris, angioedema, angiofibroma, anhidroticectodermal dysplasia-ill, anti-glomerular basement membrane disease,antigen-antibody complex mediated diseases, ankylosing spondylitis,antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis,ascites, aspergillosis, asthma, atherosclerosis, atheroscleroticplaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases,autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnalhemoglobinuria), autoimmune polyendocrinopathies, autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders,autoinflammatory diseases, back pain, Bacillus anthracis infection,Bechet's disease, bee sting-induced inflammation, Behget's syndrome,Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis,bullous pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy,carpal tunnel syndrome, Castleman's disease, catabolic disorders,cataracts, Celiac disease, cerebral aneurysm, chemical irritant-inducedinflammation, chorioretinitis, chronic atypical neutrophilic dermatosiswith lipodystrophy and elevated temperature (CANDLE) syndrome, chronicheart failure, chronic lung disease of prematurity, chronic obstructivepulmonary disease (COPD), chronic pancreatitis, chronic prostatitis,chronic recurrent multifocal osteomyelitis, cicatricial alopecia,colitis, complex regional pain syndrome, complications of organtransplantation, conjunctivitis, connective tissue disease, contactdermatitis, corneal graft neovascularization, corneal ulcer, Crohn'sdisease, cryopyrin-associated periodic syndromes, cutaneous lupuserythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of theinterleukin-1 receptor antagonist (DIRA), dermatitis, dermatitisendotoxemia, dermatomyositis, diabetic macular edema, diverticulitis,eczema, encephalitis, endometriosis, endotoxemia, eosinophilicpneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme,erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy,familial cold urticarial, familial Mediterranean fever, fetal growthretardation, fibromyalgia, fistulizing Crohn's disease, food allergies,giant cell arteritis, glaucoma, glioblastoma, glomerular disease,glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy,gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatoushepatitis, Graves' disease, growth plate injuries, Guillain-Barresyndrome. gut diseases, hair loss, Hashimoto's thyroiditis, head injury,headache, hearing loss, heart disease, hemangioma, hemolytic anemia,hemophilic joints, Henoch-Scholein purpura, hepatitis, hereditaryperiodic fever syndrome, heritable disorders of connective tissue,herpes zoster and simplex, hidradenitis suppurativa (HS), hipreplacement, Hodgkin's disease, Huntington's disease, hyaline membranedisease, hyperactive inflammatory response, hyperammonemia,hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES),hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivitypneumonitis, hypertropic bone formation, hypoplastic and other anemias,hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy,Idiopathic inflammatory myopathies (dermatomyositis, polymyositis),idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura,immunoglobulin nephropathies, immune complex nephritis, immunethrombocytopenic purpura (ITP), incontinentia pigmenti (IP,Bloch-Siemens syndrome), infectious mononucleosis, infectious diseasesincluding viral diseases such as AIDS (HIV infection), hepatitis A, B,C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatorybowel disease (IBD), inflammatory disease of the lower respiratory tractincluding bronchitis or chronic obstructive pulmonary diseases,inflammatory disease of the upper respiratory tract including the noseand sinuses such as rhinitis or sinusitis, inflammatory diseases of therespiratory tract, inflammatory ischemic event such as stroke or cardiacarrest, inflammatory lung disease, inflammatory myopathy such asmyocarditis, inflammatory liver disease, inflammatory neuropathy,inflammatory pain, insect bite-induced inflammation, interstitialcystitis, interstitial lung disease, iritis, irritant-inducedinflammation, ischemia/reperfusion, joint replacement, juvenilearthritis, juvenile rheumatoid arthritis, keratitis, kidney injurycaused by parasitic infections, kidney transplant rejection,leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS),Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupusnephritis, Lyme disease, Marfan syndrome (MFS), mast cell activationsyndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixedconnective tissue disease, Muckle-Wells syndrome (urticaria deafnessamyloidosis), mucositis, multiple organ injury syndrome, multiplesclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG),myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis,necrotizing enterocolitis, neonatal onset multisystem inflammatorydisease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis,neuropathological diseases, non-allergen induced asthma, obesity, ocularallergy, optic neuritis, organ transplant rejection, Osier-Webersyndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis,osteoporosis, osterarthritis, otitis, pachyonychia congenita, Paget'sdisease, Paget's disease of bone, pancreatitis, Parkinson's disease,pediatric rheumatology, pelvic inflammatory disease, pemphigus,pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodicfever, periodontitis, peritoneal endometriosis, pernicious anemia(Addison's disease), pertussis, PFAPA (periodic fever aphthouspharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPAsyndrome), plant irritant-induced inflammation, pneumocystis infection,pneumonia, pneumonitis, poison ivy/urushiol oil-induced inflammation,polyarthritis nodosa, polychondritis, polycystic kidney disease,polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis,reperfusion injury and transplant rejection, primary biliary cirrhosis,primary pulmonary hypertension, primary sclerosing cholangitis (PSC),proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriaticepidermis, psychosocial stress diseases, pulmonary disease, pulmonaryfibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenicgranuloma retrolental fibroplasias, pyogenic sterile arthritis,Raynaud's syndrome, Reiter's disease, reactive arthritis, renal disease,renal graft rejection, reperfusion injury, respiratory distresssyndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome,rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoidarthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis,Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis,seborrhea, sepsis, septic shock, severe pain, Sézary syndrome, sicklecell anemia, silica-induced disease (Silicosis), Sjogren's syndrome,skin diseases, skin irritation, skin rash, skin sensitization (contactdermatitis or allergic contact dermatitis), sleep apnea, spinal cordinjury, spinal stenosis, spondyloarthropathies, sports injuries, sprainsand strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoidhemorrhage, sunburn, synovial inflammation, systemic inflammatoryresponse syndrome (SIRS), systemic lupus erythematosus (SLE), systemicmast cell disease (SMCD), systemic vasculitis, systemic-onset juvenileidiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis,thrombocytopenia, thyroditis, thyroiditis, tissue transplant,toxoplasmosis, trachoma, transplantation rejection, traumatic braininjury, tuberculosis, tubulointerstitial nephritis, tumor necrosisfactor (TNF) receptor associated periodic syndrome (TRAPS), type 1diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes,ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis,vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener'sgranulomatosis, and Whipple's disease.

In some embodiments, the inflammatory condition is selected frominflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoidarthritis, glomerulonephritis, mixed connective tissue disease (MCTD),dermatomyositis, polymyositis, systemic sclerosis, antineutrophilcytoplasmic antibody-associated vasculitis, anti-phospholipid syndrome,autoimmune hemolytic anemia, macrophage activation syndrome driveninflammatory anemia, IgA nephropathy, type I diabetes, non-alcoholicsteatohepatitis, and Sjogren's syndrome. In some embodiments, theinflammatory condition is inflammatory bowel disease. In someembodiments, the inflammatory condition is psoriasis. In someembodiments, the inflammatory condition is psoriatic arthritis. In someembodiments, the inflammatory condition is rheumatoid arthritis. In someembodiments, the inflammatory condition is glomerulonephritis. In someembodiments, the inflammatory condition is mixed connective tissuedisease (MCTD). In some embodiments, the inflammatory condition isdermatomyositis. In some embodiments, the inflammatory condition ispolymyositis. In some embodiments, the inflammatory condition issystemic sclerosis. In some embodiments, the inflammatory condition isantineutrophil cytoplasmic antibody-associated vasculitis. In someembodiments, the inflammatory condition is anti-phospholipid syndrome.In some embodiments, the inflammatory condition is autoimmune hemolyticanemia. In some embodiments, the inflammatory condition is macrophageactivation syndrome driven inflammatory anemia. In some embodiments, theinflammatory condition is IgA nephropathy. In some embodiments, theinflammatory condition is type I diabetes. In some embodiments, theinflammatory condition is non-alcoholic steatohepatitis. In someembodiments, the inflammatory condition is Sjogren's syndrome.

The compounds provided herein, or pharmaceutically acceptable saltsthereof, or the pharmaceutical composition provided herein may treat orameliorate systemic lupus erythematosus (SLE), cutaneous lupuserythematosus (CLE), lupus nephritis, lupus-related, symptom of SLE,symptom of CLE, or other autoimmune disorder. Symptoms of systemic lupuserythematosus include joint pain, joint swelling, arthritis, fatigue,hair loss, mouth sores, swollen lymph nodes, sensitivity to sunlight,skin rash, headaches, numbness, tingling, seizures, vision problems,personality changes, abdominal pain, nausea, vomiting, abnormal heartrhythms, coughing up blood and difficulty breathing, patchy skin colorand Raynaud's phenomenon.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of treating systemic lupus erythematosus in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein.

In one embodiment, the present disclosure provides a compound providedherein (i.e., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein, for usein a method of treating cutaneous lupus erythematosus in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula I), or a pharmaceutically acceptable salt thereof, or atherapeutically effective amount of a pharmaceutical compositionprovided herein.

In some embodiments, the uses provided herein further compriseadministering a therapeutically effective amount of one or moreadditional therapeutic agents, or a pharmaceutically acceptable saltthereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of veltuzumab, PF-06835375,eculizumab, milatuzumab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721,AK-101, TNX-1500, theralizumab, daxdilimab, TAK-079, felzartamab,itolizumab, anifrolumab, iscalimab, dapirolizumab pegol, lanalumab,LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059,obexelimab, talacotuzumab, vobarilizumab, TE-2324, PRV-3279,chloroquine, hydroxychloroquine, hydroxychloroquine sulfate,COV-08-0064; GNKS-356, AVO-101, rozibafusp alfa, VRN-02, annexuzlimab,ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, atacicept,telitacicept, BMS-986256, M-5049, KZR-616, KPG-818, verdinexor,ALPN-303, valziflocept, LA-1, cenerimod, prednisone, corticotropin,deucravacitinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830,DV-1079, julemic acid, iberdomide, TAM-01, BML-258, brepocitinib,SDC-1801, SDC-1802, ICP-330, NTR-441, dalazatide, GSK-2646264,SKI-O-703, lanraplenib (GS-9876), GNS-1653, HMPL-523, RSLV-132,interleukin-2 follow-on biologic, interleukin-2 Anteluke, interkingrecombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylatedHLA-x (SLE), AC-0058, fenebrutinib, XNW-1011, tirabrutinibhydrochloride, branebrutinib, elsubrutinib, orelabrutinib, DWP-213388,INV-103, R-salbutamol sulphate, anchorins, NIK-SMI1, X-6, INV-17, OshadiD, baricitinib, upadacitinib, filgotinib, itacitinib, INCB-54707,delgocitinib, DWP-212525, CKD-971, as mometasone, betamethasone,forigerimod, anandamide, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710(edratide), allogeneic human umbilical cord-derived mesenchymal stemcell therapy (hUC-MSCs), LC-200, BI-705564, SM-934, GX-101, TXR-712,TXR-711, CIT-013, MHV-370, Panzyga®, TPX-6001, TPX-7001, artenimol, andAMG-592, or a pharmaceutically acceptable salt of any of the foregoing,or any combination thereof.

In some embodiments, the one or more additional therapeutic agents isselected from chloroquine and hydroxychloroquine, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the one or more additionaltherapeutic agents is chloroquine. In some embodiments, the one or moreadditional therapeutic agents is hydroxychloroquine. In someembodiments, the one or more additional therapeutic agent is apharmaceutically acceptable salt of hydroxychloroquine. In someembodiments, the one or more additional therapeutic agent ishydroxychloroquine sulfate.

In some embodiments of the uses provided herein, the subject is a human.

In some embodiments, the uses provided herein comprise administering atherapeutically effective amount of a compound provided herein (i.e., acompound of Formula I), or a pharmaceutically acceptable salt thereof.In some embodiments, the methods provided herein comprise administeringa therapeutically effective amount of a pharmaceutical compositionprovided herein.

V. Administration

The compounds of the present disclosure or pharmaceutically acceptablesalts thereof (also referred to herein as the active ingredients) can beadministered by any route appropriate to the condition to be treated.Suitable routes include oral, rectal, nasal, topical (including buccaland sublingual), transdermal, vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with, for example, the condition of the recipient. An advantageof certain compounds disclosed herein, or pharmaceutically acceptablesalts thereof, is that they are orally bioavailable and can be dosedorally.

A compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, may be administered to an individual in accordance with aneffective dosing regimen for a desired period of time or duration, suchas at least about one month, at least about 2 months, at least about 3months, at least about 6 months, or at least about 12 months or longer.In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, is administered on a daily or intermittent schedule for theduration of the individual's life.

The specific dose level of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for any particular subjectwill depend upon a variety of factors including the activity of thespecific compound employed, the age, body weight, general health, sex,diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseasein the subject undergoing therapy. For example, a dosage may beexpressed as a number of milligrams of a compound provided herein, or apharmaceutically acceptable salt thereof, per kilogram of the subject'sbody weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may beappropriate. In some embodiments, about 0.1 and 100 mg/kg may beappropriate. In other embodiments a dosage of between 0.5 and 60 mg/kgmay be appropriate. Normalizing according to the subject's body weightis particularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein, or a pharmaceutically acceptable salt thereof,administered per dose or per day. Daily dosage of a compound of FormulaI, or a pharmaceutically acceptable salt or pharmaceutically acceptabletautomer thereof, may be between about 1 mg and 4,000 mg, between about2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day,or between about 15 to 150 mg/day.

The dosage or dosing frequency of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, may be adjusted over thecourse of the treatment, based on the judgment of the administeringphysician.

The compounds of the present disclosure, or pharmaceutically acceptablesalts thereof, may be administered to an individual (e.g., a human) in atherapeutically effective amount. In some embodiments, the compound, ora pharmaceutically acceptable salt thereof, is administered once daily.

The compounds provided herein, or pharmaceutically acceptable saltsthereof, can be administered by any useful route and means, such as byoral or parenteral (e.g., intravenous) administration. Therapeuticallyeffective amounts of the compound, or a pharmaceutically acceptable saltthereof, may include from about 0.00001 mg/kg body weight per day toabout 10 mg/kg body weight per day, such as from about 0.0001 mg/kg bodyweight per day to about 10 mg/kg body weight per day, or such as fromabout 0.001 mg/kg body weight per day to about 1 mg/kg body weight perday, or such as from about 0.01 mg/kg body weight per day to about 1mg/kg body weight per day, or such as from about 0.05 mg/kg body weightper day to about 0.5 mg/kg body weight per day. In some embodiments, atherapeutically effective amount of the compounds provided herein, orpharmaceutically acceptable salts thereof, include from about 0.3 mg toabout 30 mg per day, or from about 30 mg to about 300 mg per day, orfrom about 0.3 μg to about 30 mg per day, or from about 30 μg to about300 μg per day.

A compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, may be combined with one or more additional therapeuticagents in any dosage amount of the compound of the present disclosure ora pharmaceutically acceptable salt thereof (e.g., from 1 mg to 1000 mgof compound). Therapeutically effective amounts may include from about0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg perdose to about 500 mg per dose, or such as from about 100 mg per dose toabout 400 mg per dose, or such as from about 150 mg per dose to about350 mg per dose, or such as from about 200 mg per dose to about 300 mgper dose, or such as from about 0.01 mg per dose to about 1000 mg perdose, or such as from about 0.01 mg per dose to about 100 mg per dose,or such as from about 0.1 mg per dose to about 100 mg per dose, or suchas from about 1 mg per dose to about 100 mg per dose, or such as fromabout 1 mg per dose to about 10 mg per dose, or such as from about 1 mgper dose to about 1000 mg per dose. Other therapeutically effectiveamounts of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,or about 100 mg per dose. Other therapeutically effective amounts of thecompound of the present disclosure, or pharmaceutically acceptable saltsthereof, are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675,700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about1000 mg per dose.

In some embodiments, a therapeutically effective amount of the compoundof Formula I, or a pharmaceutically acceptable salt thereof, is about 1mg to about 600 mg. In some embodiments, a therapeutically effectiveamount of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, is about 1 mg to about 500 mg. In some embodiments, atherapeutically effective amount of the compound of Formula I, or apharmaceutically acceptable salt thereof, is about 1 mg to about 400 mg.In some embodiments, a therapeutically effective amount of the compoundof Formula I, or a pharmaceutically acceptable salt thereof, is about 1mg to about 300 mg. In some embodiments, a therapeutically effectiveamount of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, is about 1 mg to about 200 mg. In some embodiments, atherapeutically effective amount of the compound of Formula I, or apharmaceutically acceptable salt thereof, is about 1 mg to about 100 mg.In some embodiments, a therapeutically effective amount of the compoundof Formula I, or a pharmaceutically acceptable salt thereof, is about 1mg to about 75 mg. In some embodiments, a therapeutically effectiveamount of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, is about 1 mg to about 50 mg. In some embodiments, atherapeutically effective amount of the compound of Formula I, or apharmaceutically acceptable salt thereof, is about 1 mg to about 25 mg.In some embodiments, a therapeutically effective amount of the compoundof Formula I, or a pharmaceutically acceptable salt thereof, is about 1mg to about 20 mg. In some embodiments, a therapeutically effectiveamount of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, is about 1 mg to about 15 mg. In some embodiments, atherapeutically effective amount of the compound of Formula I, or apharmaceutically acceptable salt thereof, is about 1 mg to about 10 mg.In some embodiments, a therapeutically effective amount of the compoundof Formula I, or a pharmaceutically acceptable salt thereof, is about 1mg to about 5 mg. In some embodiments, a therapeutically effectiveamount of the compound of Formula I, or a pharmaceutically acceptablesalt thereof, is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg,about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about22 mg, about 23 mg, about 24 mg, or about 25 mg. In some embodiments, atherapeutically effective amount of the compound of Formula I, or apharmaceutically acceptable salt thereof, is about 5 mg. In someembodiments, a therapeutically effective amount of the compound ofFormula I, or a pharmaceutically acceptable salt thereof, is about 10mg. In some embodiments, a therapeutically effective amount of thecompound of Formula I, or a pharmaceutically acceptable salt thereof, isabout 15 mg. In some embodiments, a therapeutically effective amount ofthe compound of Formula I, or a pharmaceutically acceptable saltthereof, is about 20 mg. In some embodiments, a therapeuticallyeffective amount of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is about 25 mg. In some embodiments, atherapeutically effective amount of the compound of Formula I, or apharmaceutically acceptable salt thereof, is about 30 mg. In someembodiments, a therapeutically effective amount of the compound ofFormula I, or a pharmaceutically acceptable salt thereof, is about 35mg. In some embodiments, a therapeutically effective amount of thecompound of Formula I, or a pharmaceutically acceptable salt thereof, isabout 40 mg. In some embodiments, a therapeutically effective amount ofthe compound of Formula I, or a pharmaceutically acceptable saltthereof, is about 45 mg. In some embodiments, a therapeuticallyeffective amount of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is about 50 mg.

In some embodiments, the methods described herein comprise administeringto the subject an initial daily dose of about 1 to 500 mg of a compoundprovided herein, or a pharmaceutically acceptable salt thereof, andincreasing the dose by increments until clinical efficacy is achieved.Increments of about 5, 10, 25, 50, or 100 mg can be used to increase thedose. The dosage can be increased daily, every other day, twice perweek, once per week, once every two weeks, once every three weeks, oronce a month.

When administered orally, the total daily dosage for a human subject maybe between about 1 mg and 1,000 mg, between about 10-500 mg/day, betweenabout 50-300 mg/day, between about 75-200 mg/day, or between about100-150 mg/day. In some embodiments, the total daily dosage for a humansubject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or1000 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 200, 300, 400, 500,600, 700, or 800 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about300, 400, 500, or 600 mg/day administered in a single dose.

In some embodiments, the total daily dosage for a human subject may beabout 100 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 150 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 250 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 300mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 350 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 400 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 450mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 500 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 550 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 650 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 700 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 750mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 800 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 850 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 900mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 950 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 1000 mg/day administered in a single dose.

A single dose can be administered hourly, daily, weekly, or monthly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth. In some embodiments, a compound provided herein, or apharmaceutically acceptable salt thereof, is administered once daily ina method disclosed herein. In some embodiments, a compound providedherein, or a pharmaceutically acceptable salt thereof, is administeredtwice daily in a method disclosed herein.

The frequency of dosage of the compound of the present disclosure, or apharmaceutically acceptable salt thereof, will be determined by theneeds of the individual patient and can be, for example, once per day ortwice, or more times, per day. Administration of the compound, or apharmaceutically acceptable salt thereof, continues for as long asnecessary to treat the inflammatory condition, or any other indicationdescribed herein. For example, a compound, or a pharmaceuticallyacceptable salt thereof, can be administered to a human suffering froman inflammatory condition for a period of from 20 days to 180 days or,for example, for a period of from 20 days to 90 days or, for example,for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof,followed by a period of several or more days during which a patient doesnot receive a daily dose of the compound or a pharmaceuticallyacceptable salt thereof. For example, a patient can receive a dose ofthe compound, or a pharmaceutically acceptable salt thereof, every otherday, or three times per week. Again by way of example, a patient canreceive a dose of the compound, or a pharmaceutically acceptable saltthereof, each day for a period of from 1 to 14 days, followed by aperiod of 7 to 21 days during which the patient does not receive a doseof the compound, or a pharmaceutically acceptable salt thereof, followedby a subsequent period (e.g., from 1 to 14 days) during which thepatient again receives a daily dose of the compound, or apharmaceutically acceptable salt thereof. Alternating periods ofadministration of the compound, or a pharmaceutically acceptable saltthereof, followed by non-administration of the compound, or apharmaceutically acceptable salt thereof, can be repeated as clinicallyrequired to treat the patient.

The compounds of the present disclosure, or pharmaceutically acceptablesalts thereof, or the pharmaceutical compositions of the presentdisclosure may be administered once, twice, three, or four times daily,using any suitable mode described above. Also, administration ortreatment with the compounds, or pharmaceutically acceptable saltsthereof, may be continued for a number of days; for example, commonlytreatment would continue for at least 7 days, 14 days, or 28 days, forone cycle of treatment. Treatment cycles are well known for inflammatoryconditions and other indications described herein. In some embodiments,treatment cycles are frequently alternated with resting periods of about1 to 28 days, commonly about 7 days or about 14 days, between cycles.The treatment cycles, in other embodiments, may also be continuous.

VI. Combination Therapy

Patients being treated by administration of the compounds providedherein, or pharmaceutically acceptable salts thereof, often exhibitdiseases or conditions that benefit from treatment with othertherapeutic agents. These diseases or conditions can be of aninflammatory nature or can be related to cancer, metabolic disorders,gastrointestinal disorders and the like. Thus, one embodiment of thedisclosure is a method of treating an inflammation related disease orcondition, or a metabolic disorder, gastrointestinal disorder, or cancerand the like comprising administering a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, incombination with one or more compounds useful for the treatment of suchdiseases to a subject, particularly a human subject, in need thereof.

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In some embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with two additional therapeutic agents. Insome embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In some embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In some embodiments, when a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one or moreadditional therapeutic agents as described herein, the components of thecomposition are administered as a simultaneous or sequential regimen.When administered sequentially, the combination may be administered intwo or more administrations.

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one or moreadditional therapeutic agents in a unitary dosage form for simultaneousadministration to a patient, for example as a solid dosage form for oraladministration.

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is co-administered with one ormore additional therapeutic agents.

Co-administration includes administration of unit dosages of thecompounds provided herein, or pharmaceutically acceptable salts thereof,before or after administration of unit dosages of one or more additionaltherapeutic agents. The compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be administered within seconds, minutes,or hours of the administration of one or more additional therapeuticagents. For example, in some embodiments, a unit dose of a compoundprovided herein, or a pharmaceutically acceptable salt thereof, isadministered first, followed within seconds or minutes by administrationof a unit dose of one or more additional therapeutic agents.Alternatively, in other embodiments, a unit dose of one or moreadditional therapeutic agents is administered first, followed byadministration of a unit dose of a compound provided herein, or apharmaceutically acceptable salt thereof, within seconds or minutes. Insome embodiments, a unit dose of a compound provided herein, or apharmaceutically acceptable salt thereof, is administered first,followed, after a period of hours (i.e., 1-12 hours), by administrationof a unit dose of one or more additional therapeutic agents. In otherembodiments, a unit dose of one or more additional therapeutic agents isadministered first, followed, after a period of hours (i.e., 1-12hours), by administration of a unit dose of a compound provided hereinor a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is formulated as a tablet, which may optionallycontain one or more other compounds useful for treating the diseasebeing treated. In certain embodiments, the tablet can contain anotheractive ingredient for treating an inflammatory condition or otherindication described herein. In some embodiments, such tablets aresuitable for once daily dosing.

Also provided herein are methods of treatment in which a compound ofFormula I, or a tautomer or pharmaceutically acceptable salt thereof, isgiven to a patient in combination with one or more additionaltherapeutic agents or therapy. In some embodiments, the total dailydosage of a compound of Formula I, or a tautomer, or a pharmaceuticallyacceptable salt thereof, may be about 1 to about 500 mg/day administeredin a single dose for a human subject.

Inflammatory Condition or Disease Combination Therapy

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one or more additionaltherapeutic agents that treat or ameliorate an inflammatory condition.Non-limiting examples of an inflammatory condition include, withoutlimitation, acne, acid-induced lung injury, Addison's disease, adrenalhyperplasia, adrenocortical insufficiency, adult-onset Still's disease,adult respiratory distress syndrome (ARDS), age-related maculardegeneration, aging, alcoholic hepatitis, alcoholic liver disease,allergen-induced asthma, allergic bronchopulmonary, allergicconjunctivitis, allergic contact dermatitis, allergies, allergicencephalomyelitis, allergic neuritis, allograft rejection, alopecia,alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateralsclerosis, angina pectoris, angioedema, angiofibroma, anhidroticectodermal dysplasia-ill, anti-glomerular basement membrane disease,antigen-antibody complex mediated diseases, ankylosing spondylitis,antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis,ascites, aspergillosis, asthma, atherosclerosis, atheroscleroticplaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases,autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnalhemoglobinuria), autoimmune polyendocrinopathies, autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders,autoinflammatory diseases, back pain, Bacillus anthracis infection,Bechet's disease, bee sting-induced inflammation, Behget's syndrome,Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis,bullous pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy,carpal tunnel syndrome, Castleman's disease, catabolic disorders,cataracts, Celiac disease, cerebral aneurysm, chemical irritant-inducedinflammation, chorioretinitis, chronic atypical neutrophilic dermatosiswith lipodystrophy and elevated temperature (CANDLE) syndrome, chronicheart failure, chronic lung disease of prematurity, chronic obstructivepulmonary disease (COPD), chronic pancreatitis, chronic prostatitis,chronic recurrent multifocal osteomyelitis, cicatricial alopecia,colitis, complex regional pain syndrome, complications of organtransplantation, conjunctivitis, connective tissue disease, contactdermatitis, corneal graft neovascularization, corneal ulcer, Crohn'sdisease, cryopyrin-associated periodic syndromes, cutaneous lupuserythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of theinterleukin-1 receptor antagonist (DIRA), dermatitis, dermatitisendotoxemia, dermatomyositis, diabetic macular edema, diverticulitis,eczema, encephalitis, endometriosis, endotoxemia, eosinophilicpneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme,erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy,familial cold urticarial, familial Mediterranean fever, fetal growthretardation, fibromyalgia, fistulizing Crohn's disease, food allergies,giant cell arteritis, glaucoma, glioblastoma, glomerular disease,glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy,gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatoushepatitis, Graves' disease, growth plate injuries, Guillain-Barresyndrome. gut diseases, hair loss, Hashimoto's thyroiditis, head injury,headache, hearing loss, heart disease, hemangioma, hemolytic anemia,hemophilic joints, Henoch-Scholein purpura, hepatitis, hereditaryperiodic fever syndrome, heritable disorders of connective tissue,herpes zoster and simplex, hidradenitis suppurativa (HS), hipreplacement, Hodgkin's disease, Huntington's disease, hyaline membranedisease, hyperactive inflammatory response, hyperammonemia,hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES),hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivitypneumonitis, hypertropic bone formation, hypoplastic and other anemias,hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy,Idiopathic inflammatory myopathies (dermatomyositis, polymyositis),idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura,immunoglobulin nephropathies, immune complex nephritis, immunethrombocytopenic purpura (ITP), incontinentia pigmenti (IP,Bloch-Siemens syndrome), infectious mononucleosis, infectious diseasesincluding viral diseases such as AIDS (HIV infection), hepatitis A, B,C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatorybowel disease (IBD), inflammatory disease of the lower respiratory tractincluding bronchitis or chronic obstructive pulmonary diseases,inflammatory disease of the upper respiratory tract including the noseand sinuses such as rhinitis or sinusitis, inflammatory diseases of therespiratory tract, inflammatory ischemic event such as stroke or cardiacarrest, inflammatory lung disease, inflammatory myopathy such asmyocarditis, inflammatory liver disease, inflammatory neuropathy,inflammatory pain, insect bite-induced inflammation, interstitialcystitis, interstitial lung disease, iritis, irritant-inducedinflammation, ischemia/reperfusion, joint replacement, juvenilearthritis, juvenile rheumatoid arthritis, keratitis, kidney injurycaused by parasitic infections, kidney transplant rejection,leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS),Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupusnephritis, Lyme disease, Marfan syndrome (MFS), mast cell activationsyndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixedconnective tissue disease, Muckle-Wells syndrome (urticaria deafnessamyloidosis), mucositis, multiple organ injury syndrome, multiplesclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG),myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis,necrotizing enterocolitis, neonatal onset multisystem inflammatorydisease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis,neuropathological diseases, non-allergen induced asthma, obesity, ocularallergy, optic neuritis, organ transplant rejection, Osier-Webersyndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis,osteoporosis, osterarthritis, otitis, pachyonychia congenita, Paget'sdisease, Paget's disease of bone, pancreatitis, Parkinson's disease,pediatric rheumatology, pelvic inflammatory disease, pemphigus,pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodicfever, periodontitis, peritoneal endometriosis, pernicious anemia(Addison's disease), pertussis, PFAPA (periodic fever aphthouspharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPAsyndrome), plant irritant-induced inflammation, pneumocystis infection,pneumonia, pneumonitis, poison ivy/urushiol oil-induced inflammation,polyarthritis nodosa, polychondritis, polycystic kidney disease,polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis,reperfusion injury and transplant rejection, primary biliary cirrhosis,primary pulmonary hypertension, primary sclerosing cholangitis (PSC),proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriaticepidermis, psychosocial stress diseases, pulmonary disease, pulmonaryfibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenicgranuloma retrolental fibroplasias, pyogenic sterile arthritis,Raynaud's syndrome, Reiter's disease, reactive arthritis, renal disease,renal graft rejection, reperfusion injury, respiratory distresssyndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome,rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoidarthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis,Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis,seborrhea, sepsis, septic shock, severe pain, Sézary syndrome, sicklecell anemia, silica-induced disease (Silicosis), Sjogren's syndrome,skin diseases, skin irritation, skin rash, skin sensitization (contactdermatitis or allergic contact dermatitis), sleep apnea, spinal cordinjury, spinal stenosis, spondyloarthropathies, sports injuries, sprainsand strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoidhemorrhage, sunburn, synovial inflammation, systemic inflammatoryresponse syndrome (SIRS), systemic lupus erythematosus (SLE), systemicmast cell disease (SMCD), systemic vasculitis, systemic-onset juvenileidiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis,thrombocytopenia, thyroditis, thyroiditis, tissue transplant,toxoplasmosis, trachoma, transplantation rejection, traumatic braininjury, tuberculosis, tubulointerstitial nephritis, tumor necrosisfactor (TNF) receptor associated periodic syndrome (TRAPS), type 1diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes,ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis,vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener'sgranulomatosis, and Whipple's disease.

Non-limiting examples of therapeutic agents for treatment of aninflammatory disease or condition that can be used in combination withthe compounds provided herein, or pharmaceutically acceptable saltsthereof, include alpha-fetoprotein modulators; adenosine A3 receptorantagonist; adrenomedullin ligands; AKT1 gene inhibitors; antibiotics;antifungals; ASK1 inhibitors; ATPase inhibitors; beta adrenoceptorantagonists; BTK inhibitors; calcineurin inhibitors; carbohydratemetabolism modulators; cathepsin S inhibitors; CCR9 chemokineantagonists; CD233 modulators; CD29 modulators; CD3 antagonists; CD40ligand inhibitors; CD40 ligand receptor antagonists; chemokine CXCligand inhibitors; CHST15 gene inhibitors; collagen modulators; COTprotein kinase inhibitors; CSF-1 agonist; CSF-1 antagonists; CX3CR1chemokine modulators DYRK-1 alpha protein kinase inhibitor, eotaxinligand inhibitors; EP4 prostanoid receptor agonists; F1F0 ATP synthasemodulators; farnesoid X receptor (FXR, NR1H4) agonists or modulators;fecal microbiota transplantation (FMT), fractalkine ligand inhibitors;free fatty acid receptor 2 antagonists; GATA 3 transcription factorinhibitors; glucagon-like peptide 2 agonists; glucocorticoid agonists;Glucocorticoid receptor modulators; guanylate cyclase receptor agonists;HIF prolyl hydroxylase inhibitors; histone deacetylase inhibitors; HLAclass II antigen modulators; hypoxia inducible factor-1 stimulator;ICAM1 gene inhibitors; IL-1 beta ligand modulators; IL-12 antagonists;IL-13 antagonists; IL-18 antagonists; IL-18 receptor accessory proteinantagonist, IL-22 agonists; IL-23 antagonists; IL-23A inhibitors; IL-6antagonists; IL-7 receptor antagonists; IL-8 receptor antagonists; IL-36inhibitors, integrin alpha-4/beta-1 antagonists; integrin alpha-4/beta-7antagonists; integrin antagonists; interleukin ligand inhibitors;interleukin receptor 17A antagonists; interleukin-1 beta ligands;interleukin 1 like receptor 2 inhibitors; IL-6 receptor modulators; JAKtyrosine kinase inhibitors; Jak1 tyrosine kinase inhibitors; Jak3tyrosine kinase inhibitors; lactoferrin stimulators; LanC like protein 2modulators; leukocyte elastate inhibitors; leukocyte proteinase-3inhibitors; MAdCAM inhibitors; melanin concentrating hormone (MCH-1)antagonist; melanocortin agonists; metalloprotease-9 inhibitors;microbiome-targeting therapeutics; natriuretic peptide receptor Cagonists; neuregulin-4 ligands; NLRP3 inhibitors; NKG2 D activating NKreceptor antagonists; NR1H4 receptor (FXR) agonists or modulators(deleted); nuclear factor kappa B inhibitors; opioid receptorantagonists; OX40 ligand inhibitors; oxidoreductase inhibitors; P2X7purinoceptor modulators; PDE 4 inhibitors; Pellino homolog 1 inhibitors;PPAR alpha/delta agonists; PPAR gamma agonists; Protein argininedeiminase IV inhibitor, protein fimH inhibitors; P-selectin glycoproteinligand-1 inhibitors; Ret tyrosine kinase receptor inhibitors; RIP-1kinase inhibitors; RIP-2 kinase inhibitors; RNA polymerase inhibitors;sphingosine 1 phosphate phosphatase 1 stimulators;sphingosine-1-phosphate receptor-1 agonists; sphingosine-1-phosphatereceptor-5 agonists; sphingosine-1-phosphate receptor-1 antagonists;sphingosine-1-phosphate receptor-1 modulators; stem cell antigen-1inhibitors; superoxide dismutase modulators; SYK inhibitors; tissuetransglutaminase inhibitor; TLR-3 antagonists; TLR-4 antagonists;Toll-like receptor 8 (TLR8) inhibitors; TNF alpha ligand inhibitors; TNFligand inhibitors; TNF alpha ligand modulators; TNF antagonists; TPL-2inhibitors; tumor necrosis factor 14 ligand modulators; tumor necrosisfactor 15 ligand inhibitors; Tyk2 tyrosine kinase inhibitors; type IIL-1 receptor antagonists; vanilloid VR1 agonists; and zonulininhibitors; or any combination thereof.

Adenosine A3 receptor antagonists include but are not limited toPBF-677.

Adrenomedullin ligands include but are not limited to adrenomedullin.

Antibiotics include but are not limited to ciprofloxacin,clarithromycin, metronidazole, vancomycin, rifamycin, rifaximin, andtosufloxacin.

ASK1 inhibitors include but are not limited to GS-4997.

Alpha-fetoprotein modulators include but are not limited to ACT-101.

Anti-CD28 inhibitors include but are not limited to JNJ-3133 andabatacept.

Beta adrenoceptor antagonists include but are not limited to NM-001.

BTK inhibitors include but are not limited to GS-4059.

Calcineurin inhibitors include but are not limited to tacrolimus andciclosporin.

Carbohydrate metabolism modulators include but are not limited toASD-003.

Cathepsin S inhibitors include but are not limited to VBY-129.

CCR9 chemokine antagonists include but are not limited to CCX-507.

CD233 modulators include but are not limited to GSK-2831781.

CD29 modulators include but are not limited to PF-06687234.

CD3 antagonists include but are not limited to NI-0401, muromonab-CD3,and teplizumab.

CD4 antagonists include but are not limited to IT-1208.

CD40 ligand inhibitors include but are not limited to SAR-441344 andletolizumab.

CD40 gene inhibitors include but are not limited to NJA-730.

CD40 ligand receptor antagonists include but are not limited to FFP-104,BI-655064, ABBV-323, and VIB-4920.

Chaperonin binding immunoglobulin protein include but are not limited toIRL-201805.

Chemokine CXC ligand inhibitors include but are not limited toLY-3041658.

CHST15 gene inhibitors include but are not limited to STNM-01.

Collagen modulators include but are not limited to ECCS-50 (DCCT-10).

COT protein kinase inhibitors include but are not limited to GS-4875.

CSF-1 antagonists include but are not limited to JNJ-40346527 (PRV-6527)and SNDX-6352.

CX3CR1 chemokine modulators include but are not limited to E-6130.

DYRK-1 alpha protein kinase inhibitor include but are not limited toVRN-02.

Microbiome-targeting therapeutics include but are not limited toSER-287, SER-301, and SER-155.

Eotaxin ligand inhibitors include but are not limited to bertilimumab.

EP4 prostanoid receptor agonists include but are not limited to KAG-308.

FIFO ATP synthase modulators include but are not limited to LYC-30937EC.

Fractalkine ligand inhibitors include but are not limited to quetmolimab(E-6011).

Free fatty acid receptor 2 antagonists include but are not limited toGLPG-0974.

GATA 3 transcription factor inhibitors include but are not limited toSB-012.

Glucagon-like peptide 2 agonists include but are not limited toteduglutide and apraglutide.

Glucocorticoid receptor agonists include but are not limited tobudesonide, beclomethasone dipropionate, and dexamethasone sodiumphosphate.

Glucocorticoid receptor modulators/TNF ligand inhibitors include but arenot limited to ABBV-3373.

Guanylate cyclase receptor agonists include but are not limited todolcanatide.

HIF prolyl hydroxylase inhibitors include but are not limited to DS-1093and AKB-4924.

HIF prolyl hydroxylase-2 inhibitors/hypoxia inducible factor-1stimulators include but are not limited to GB-004.

Histone deacetylase inhibitors include but are not limited to givinostatand NIPEP-CARE.

Histone deacetylase-6 inhibitors include but are not limited to CKD-506.

HLA class II antigen modulators include but are not limited to HLA classII protein modulators.

ICAM1 gene inhibitors include but are not limited to alicaforsen.

IL-12 antagonists include but are not limited to ustekinumab(IL12/IL23).

IL-13 antagonists include but are not limited to tralokinumab.

IL-18 antagonists include but are not limited to GSK-1070806.

IL-18 receptor accessory protein antagonist include but are not limitedto anti-IL-1R7 canonical antibody.

IL-22 agonists include but are not limited to AMT-126 and RG-7880.

IL-23 antagonists include but are not limited to tildrakizumab,risankizumab (BI-655066), mirikizumab (LY-3074828), brazikumab(AMG-139), IBI-112, and PTG-200.

IL-23A inhibitors include but are not limited to guselkumab.

IL-6 antagonists include but are not limited to olokizumab.

IL-7 receptor antagonists include but are not limited to OSE-127.

IL-8 receptor antagonists include but are not limited to clotrimazole.

Integrin alpha-4/beta-1 antagonists include but are not limited tonatalizumab.

Integrin alpha-4/beta-7 antagonists include but are not limited toetrolizumab (a4b7/aEb7), vedolizumab, carotegrast methyl, TRK-170(a4b7/a4b1), PTG-100, and PN-10943.

Integrin antagonists include but are not limited to E-6007.

Interleukin ligand inhibitors include but are not limited to bimekizumab(IL-17A/IL-17F).

Interleukin receptor 17A antagonists include but are not limited tobrodalumab.

Interleukin-1 beta ligands include but are not limited to K(D)PT.

Interleukin 1 like receptor 2 inhibitors include but are not limited toBI-655130.

IL-6 receptor modulators include but are not limited to Amilo-5MER andolamkicept.

JAK tyrosine kinase inhibitors include but are not limited totofacitinib (1/3), peficitinib (1/3), TD-3504, and TD-1473.

Jak1 tyrosine kinase inhibitors include but are not limited to acompound disclosed in U.S. Pat. No. 9,238,628.

Jak3 tyrosine kinase inhibitors include but are not limited to OST-122and PF-06651600.

Jak3 tyrosine kinase inhibitor/TrkA receptor antagonist include but arenot limited to SNA-125.

Examples of other JAK inhibitors include but are not limited to AT9283,AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634),gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387),NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib,tofacitinib (formerly tasocitinib), XL019, upadacitinib (ABT-494),LPG-0555, SHR-0302, and brepocitinib (PF-06700841) (JAK1/Tyk2).

Lactoferrin stimulators include but are not limited to recombinant humanlactoferrin (VEN-100).

LanC like protein 2 modulators include but are not limited to BT-11 andBT-104.

Leukocyte elastase inhibitors/Leukocyte proteinase-3 inhibitors includebut are not limited to tiprelestat.

MAdCAM inhibitors include but are not limited to SHP-647 (PF-547659).

Melanin concentrating hormone (MCH-1) antagonists include but are notlimited to CSTI-100.

Melanocortin MCi receptor agonists include but are not limited toASP-3291 and PL-8177.

Metalloprotease-9 inhibitors include but are not limited to GS-5745.

Microbiome modulators include but are not limited to ABI-M201.

Natriuretic peptide receptor C agonists include but are not limited toplecanatide.

Neuregulin-4 ligands include but are not limited to NRG-4.

NKG2 D activating NK receptor antagonists include but are not limited toJNJ-4500.

NLRP3 inhibitors include but are not limited to dapansutrile,BMS-986299, SB-414, MCC-950, IFM-514, JT-194, PELA-167, and NBC-6.

Farnesoid X receptor (FXR, NR1H4) agonists or modulators include but arenot limited to AGN-242266, cilofexor tromethamine (GS-9674), EDP-305,EYP-001, GNF-5120, MET-409, MET-642, nidufexor (LMB-763), obeticholicacid, TERN-101, and tropifexor.

Nuclear factor kappa B inhibitors include but are not limited toThetanix.

Opioid receptor antagonists include but are not limited to naltrexoneand IRT-103.

OX40 ligand inhibitors include but are not limited to KHK-4083.

Oxidoreductase inhibitors include but are not limited to olsalazine.

Pellino homolog 1 inhibitors include but are not limited to BBT-401.

P2X7 purinoceptor modulators include but are not limited to SGM-1019.

PDE 4 inhibitors include but are not limited to apremilast.

PPAR alpha/delta agonists include but are not limited to elafibranor(GFT-1007).

PPAR gamma agonists include but are not limited to GED-0507-34-Levo.

Protein fimH inhibitors include but are not limited to sibofimloc(EB-8018).

P-selectin glycoprotein ligand-1 inhibitors include but are not limitedto SEL-K2, AbGn-168H, and neihulizumab.

Ret tyrosine kinase receptor inhibitors include but are not limited toGSK-3179106.

RIP-1 kinase inhibitors include but are not limited to GSK-2982772 andVRN-04.

RIP-2 kinase inhibitors include but are not limited to GSK-2983559.

Sphingosine 1 phosphate phosphatase 1 stimulators include but are notlimited to etrasimod.

Sphingosine-1-phosphate receptor-1 agonists include but are not limitedto mocravimod (KRP-203) and BMS-986166.

Sphingosine-1-phosphate receptor-1 agonists/Sphingosine-1-phosphatereceptor-5 agonists include but are not limited to ozanimod.

Sphingosine-1-phosphate receptor-1 antagonists include but are notlimited to amiselimod (MT-1303).

Sphingosine-1-phosphate receptor-1 modulators include but are notlimited to OPL-002, SK1-I.

Stem cell antigen-1 inhibitors include but are not limited to Ampion(DMI-9523).

Superoxide dismutase modulators include but are not limited tomidismase.

Syk inhibitors include but are not limited to GS-9876.

tissue transglutaminase inhibitor include but are not limited tozampilimab

TLR-3 antagonists include but are not limited to PRV-300.

TLR-4 antagonists include but are not limited to JKB-122.

Toll-like receptor 8 (TLR8) inhibitors include but are not limited toE-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod,resiquimod, VTX-1463, and VTX-763.

TNF alpha ligand inhibitors include but are not limited to adalimumab,certolizumab pegol, infliximab, golimumab, DLX-105, Debio-0512,HMPL-004, CYT-020-TNFQb, Hemay-007, and V-565.

TNF alpha ligand modulators/IL-1 beta ligand modulators include but arenot limited to PUR-0110.

TNF antagonists include but are not limited to AVX-470, tulinercept, andetanercept.

Tumor necrosis factor 14 ligand modulators include but are not limitedto AEVI-002.

Tumor necrosis factor 15 ligand inhibitors include but are not limitedto PF-06480605.

Tyk2 tyrosine kinase inhibitors include but are not limited toPF-06826647 and BMS-986165.

Type I IL-1 receptor antagonists include but are not limited toanakinra.

Zonulin inhibitors include but are not limited to larazotide acetate.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one or moreanti-inflammatory agents. Anti-inflammatory agents include but are notlimited to non-steroidal anti-inflammatory drugs (NSAIDs), non-specificand COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds,corticosteroids, methotrexate, tumor necrosis factor receptor (TNF)receptors antagonists, and immunosuppressants.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Additional examples of NSAIDs also include but arenot limited to COX-2 specific inhibitors (i.e., a compound that inhibitsCOX-2 with an IC₅₀ that is at least 50-fold lower than the IC₅₀ forCOX-1), such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/orrofecoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, choline, and magnesium salicylates.

In some embodiments, the anti-inflammatory agent is a corticosteroid.Non-limiting examples of a corticosteroid include cortisone,dexamethasone, methylprednisolone, prednisolone, prednisolone sodiumphosphate, and prednisone.

In some embodiments, the anti-inflammatory agent is a gold compound,e.g., gold sodium thiomalate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolicinhibitor. Non-limiting examples of a metabolic inhibitor include adihydrofolate reductase inhibitor, such as methotrexate, or adihydroorotate dehydrogenase (DHODH) inhibitor, such as leflunomide.

In some embodiments, the anti-inflammatory agent is an anti-C5monoclonal antibody (such as eculizumab or pexelizumab), a TNFantagonist (such as entanercept), or infliximab, which is an anti-TNFalpha monoclonal antibody.

In some embodiments, the anti-inflammatory agent is animmunosuppressant. Non-limiting examples of an immunosuppressant includemethotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine,mycophenolate sodium, mercaptopurine, and mycophenolate mofetil.

Lupus Combination Therapy

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, is combined with one or more additionaltherapeutic agents that target adenosylhomocysteinase, ADP ribosylcyclase-1 (CD38), adrenocorticotrophic hormone ligands, AIMPmultisynthetase complex protein 1, annexin A1 modulators, B and Tlymphocyte attenuator (BTLA), BDCA2, beta 2 adrenoceptor, B-lymphocyteantigen CD19, B-lymphocyte antigen CD20, B-lymphocyte cell adhesionmolecule (CD22), B-lymphocyte stimulator ligand (BAFF), btk tyrosinekinase, cannabinoid CB2 receptor, CD11b agonists, CD38Activation-inducible TNF receptor, CD40 (CD154) ligand, CD74, CD79bmodulators, CDw123, Collagen VII (Col VII), Complement C5 factor, C-typelectin domain protein 4C, CXCR5 chemokine modulators, deoxyribonucleasemodulators, DNA binding protein Ikaros, DYRK-1 alpha protein kinase,dndoplasmin, Exportin 1, FK506 binding protein, glucocorticoid receptor,HLA antigen, IL-10, IL-23m IL-12 receptors, IL-2 receptor, IL-2 receptoralpha subunit, IL-21 modulators, IL-6R, immunoglobulin gamma Fc receptorII modulators, immunoglobulin gamma Fc receptor IIB, inducible T-cellco-stimulator, interferon alpha ligand (INF-alpha), interferon omegaligand (INF omega), interferon type I receptor, interleukin-2 ligand,Itk tyrosine kinase, JAK tyrosine kinase, Jak1 tyrosine kinase, Jak2tyrosine kinase, Jak3 tyrosine kinase, KCNA voltage-gated potassiumchannel-3, leukocyte Ig like receptor A4 modulators, mitochondrial 10kDa heat shock protein, mTOR, non receptor tyrosine kinase TYK2, nuclearexport, nuclear factor kappa B inducing kinase, nuclease stimulators,OX-40 receptors, PARP modulators, proteasome modulators, proteinarginine deiminase IV (PAD4), protein cereblon modulators, proteinMB21D1, retinoid Z receptor gamma inverse, rho associated protein kinase1, rho associated protein kinase 2, serine threonine protein kinase TBK1(TBK1), sphingosine kinase 1, sphingosine-1-phosphate receptor-1modulators, stimulator of interferon genes protein, Syk tyrosine kinase,T cell surface glycoprotein CD28, T-cell differentiation antigen CD6,TLR-7 modulators, TLR-8 modulators, TLR-9 modulators, transcriptionfactor modulators, tumor necrosis factor ligand 13 (APRIL), Tyk2tyrosine kinase, ubiquitin ligase modulators, and/or zinc finger bindingprotein Aiolos.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents selected from:

-   -   activation-inducible TNF receptor agonists, including but not        limited to BMS-986256;    -   adenosylhomocysteinase inhibitors, including but not limited to        DZ-2002;    -   adrenocorticotrophic hormone ligands, including but not limited        to corticotropin;    -   AIMP multisynthetase complex protein 1 stimulator/Endoplasmin        inhibitors, including but not limited to anchorins;    -   anti-CDw123 antibodies, including but not limited to        talacotuzumab;    -   annexin A1 modulators, including but not limited to        annexuzlimab;    -   anti-IL-12/IL23 antibodies, including but not limited to AK-101;    -   anti-BAFF-R antibodies, including but not limited to lanalumab;    -   anti-BDCA2 antibodies, including but not limited to BIIB-059;    -   anti-BLys antibodies, including but not limited to belimumab and        UBP-1213;    -   anti-BTLA modulator antibodies, including but not limited to        LY-3361237;    -   anti-C5 antibodies, including but not limited to eculizumab;    -   anti-CD154 antibodies, including but not limited to TNX-1500;    -   anti-CD19/CD32b antibodies, including but not limited to        obexelimab;    -   anti-CD20 antibodies, including but not limited to veltuzumab;    -   anti-CD22 antibodies, including but not limited to SM-06, SM-03;    -   anti-CD28 antibodies, including but not limited to theralizumab;    -   anti-CD38 antibodies, including but not limited to TAK-079 and        felzartamab;    -   anti-CD40 antibodies, including but not limited to iscalimab and        dapirolizumab pegol;    -   anti-CD6 antibodies, including but not limited to itolizumab;    -   anti-CD74 antibodies, including but not limited to milatuzumab;    -   anti-CXCR5 antibodies, including but not limited to PF-06835375;    -   anti-IFN-alpha antibodies, including but not limited to        QX-006-N;    -   anti-IFN-alpha/omega antibodies, including but not limited to        JNJ-55920839;    -   anti-IL-10 antibodies, including but not limited to BT-063;    -   anti-IL-21 antibodies, including but not limited to BOS-161721;    -   anti-IL-6R nanobodies, including but not limited to        vobarilizumab;    -   anti-ILT7 antibodies, including but not limited to daxdilimab;    -   anti-interferon alpha vaccines, including but not limited to        CKD-971;    -   anti-interferon receptor type I antibodies, including but not        limited to anifrolumab;    -   anti-PAD4 antibodies, including but not limited to PFI-102;    -   anti-TLR-7 antibodies, including but not limited to DS-7011;    -   BAFF/APRIL inhibitors, including but not limited to ALPN-303;    -   Beta 2 adrenoceptor agonists, including but not limited to        R-salbutamol sulphate;    -   bi-specific antibodies targeting BAFF/ICOSL, including but not        limited to rozibafusp alfa;    -   bi-specific antibodies targeting CD32B/CD79B, including but not        limited to PRV-3279;    -   bi-specific antibodies targeting Col VII/BAFF, including but not        limited to TE-2324;    -   B-lymphocyte stimulator ligand inhibitors, including but not        limited to atacicept and telitacicept;    -   Btk tyrosine kinase inhibitors, including but not limited to        AC-0058, fenebrutinib, XNW-1011, tirabrutinib hydrochloride,        branebrutinib, elsubrutinib, and orelabrutinib;    -   Btk/itk tyrosine kinase inhibitors, including but not limited to        DWP-213388;    -   Btk/Jak3 tyrosine kinase inhibitors, including but not limited        to DWP-212525;    -   cannabinoid CB2 receptor agonists, including but not limited to        julemic acid;    -   CD11b agonists, including but not limited to LA-1;    -   deoxyribonuclease gamma stimulators, including but not limited        to NTR-441;    -   deoxyribonuclease modulators, including but not limited to        Oshadi D;    -   DYRK-1 alpha protein kinase inhibitors, including but not        limited to VRN-02;    -   exportin 1 inhibitors, including but not limited to SINE        compounds;    -   glucocorticoid receptor agonists, including but not limited to        prednisone;    -   HLA antigen modulators, including but not limited to PEGylated        HLA-x (SLE);    -   IL-2 receptor alpha subunit stimulators, including but not        limited to NKTR-35;    -   immunoglobulin gamma Fc receptor IIB modulators, including but        not limited to valziflocept;    -   inducible T-cell co-stimulator inhibitor (ICOS)/T cell surface        glycoprotein CD28 inhibitors, including but not limited to        ALPN-101;    -   interferon alpha ligand modulator/TLR-7/TLR-9 modulators,        including but not limited to DV-1079;    -   interleukin-2 ligands, including but not limited to        interleukin-2 Anteluke, interking recombinant human        interleukin-2, ILT-101, and CUG-252;    -   interleukin-2 ligands/IL-2 receptor agonists, including but not        limited to interleukin-2 follow-on biologic;    -   JAK 1/2/3 and ROCK 1/2 inhibitors, including but not limited to        CPL-409116;    -   JAK tyrosine kinase inhibitors, including but not limited to        delgocitinib;    -   Jak1/Jak2 tyrosine kinase inhibitors, including but not limited        to baricitinib;    -   Jak1 tyrosine kinase inhibitors, including but not limited to        upadacitinib, filgotinib, itacitinib, and INCB-54707;    -   Jak1/Tyk2 tyrosine kinase inhibitors, including but not limited        to brepocitinib, SDC-1801, and SDC-1802;    -   JAK3/1 and TBK1 kinase inhibitors, including but not limited to        CS-12192;    -   JAK3/JAK1 tyrosine kinase inhibitors, including but not limited        to tofacitinib citrate;    -   KCNA voltage-gated potassium channel-3 inhibitors, including but        not limited to dalazatide;    -   mitochondrial 10 kDa heat shock protein stimulators, including        but not limited to INV-103;    -   mTOR inhibitors, including but not limited to TAM-01;    -   non-receptor tyrosine kinase TYK2 antagonists, including but not        limited to ICP-330;    -   nuclear export inhibitors, including but not limited to        verdinexor;    -   nuclear factor kappa B inducing kinase inhibitors, including but        not limited to NIK-SMI1;    -   nuclease stimulators, including but not limited to RSLV-132;    -   OX-40 receptor antagonists, including but not limited to        ISB-830;    -   PARP modulators, including but not limited to bendamustine        hydrochloride;    -   PD-L1 CAR-expressing NK-92 cell therapy;    -   proteasome inhibitors, including but not limited to KZR-616;    -   protein cereblon modulators, including but not limited to        iberdomide;    -   protein MB21D1 inhibitors, including but not limited to X-6;    -   retinoid Z receptor gamma inverse agonists, including but not        limited to INV-17;    -   sphingosine kinase 1 inhibitors, including but not limited to        BML-258;    -   sphingosine-1-phosphate receptor-1 modulator, including but not        limited to cenerimod;    -   Syk tyrosine kinase inhibitors, including but not limited to        GSK-2646264, SKI-O-703, lanraplenib (GS-9876), GNS-1653, and        HMPL-523;    -   TLR-9 antagonists, including but not limited to chloroquine,        hydroxychloroquine, hydroxychloroquine sulfate, COV-08-0064;        GNKS-356, and AVO-101;    -   TLR7/8 antagonists, including but not limited to M-5049, E-6887,        and BMS-986256;    -   TLR-8 antagonists, including but not limited to ZG-170607;    -   TLR7/8/9 antagonists, including but not limited to IMO-8400 and        IMO-9200;    -   Tyk2 tyrosine kinase inhibitors, including but not limited to        deucravacitinib;    -   ubiquitin ligase modulators, including but not limited to        KPG-818; and    -   other drugs for lupus, including but not limited to mometasone,        betamethasone, forigerimod, anandamide, DCB-SLE1, arsenic        trioxide, tairuimide, TV-4710 (edratide), allogeneic human        umbilical cord-derived mesenchymal stem cell therapy (hUC-MSCs),        LC-200, BI-705564, SM-934, GX-101, TXR-712, TXR-711, CIT-013,        MHV-370, Panzyga®, TPX-6001, TPX-7001, artenimol, AMG-592,        phosphatidylserine-liposome-based immunotherapy, and        CD4+CD127lo/-CD25+ polyclonal regulatory T cells.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents selected from veltuzumab, PF-06835375,eculizumab, milatuzumab, SM-06, SM-03, BT-063, QX-006-N, BOS-161721,AK-101, TNX-1500, theralizumab, daxdilimab, TAK-079, felzartamab,itolizumab, anifrolumab, iscalimab, dapirolizumab pegol, lanalumab,LY-3361237, JNJ-55920839, UBP-1213, DS-7011, PFI-102, BIIB-059,obexelimab, talacotuzumab, vobarilizumab, TE-2324, PRV-3279,chloroquine, hydroxychloroquine, hydroxychloroquine sulfate,COV-08-0064; GNKS-356, AVO-101, rozibafusp alfa, VRN-02, annexuzlimab,ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35, atacicept,telitacicept, BMS-986256, M-5049, KZR-616, KPG-818, verdinexor,ALPN-303, valziflocept, LA-1, cenerimod, prednisone, corticotropin,deucravacitinib, CPL-409116, CS-12192, tofacitinib citrate, ISB-830,DV-1079, julemic acid, iberdomide, TAM-01, BML-258, brepocitinib,SDC-1801, SDC-1802, ICP-330, NTR-441, dalazatide, GSK-2646264,SKI-O-703, lanraplenib (GS-9876), GNS-1653, HMPL-523, RSLV-132,interleukin-2 follow-on biologic, interleukin-2 Anteluke, interkingrecombinant human interleukin-2, ILT-101, CUG-252, DZ-2002, PEGylatedHLA-x (SLE), AC-0058, fenebrutinib, XNW-1011, tirabrutinibhydrochloride, branebrutinib, elsubrutinib, orelabrutinib, DWP-213388,INV-103, R-salbutamol sulphate, anchorins, NIK-SMI1, X-6, INV-17, OshadiD, baricitinib, upadacitinib, filgotinib, itacitinib, INCB-54707,delgocitinib, DWP-212525, CKD-971, as mometasone, betamethasone,forigerimod, anandamide, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710(edratide), allogeneic human umbilical cord-derived mesenchymal stemcell therapy (hUC-MSCs), LC-200, BI-705564, SM-934, GX-101, TXR-712,TXR-711, CIT-013, MHV-370, Panzyga®, TPX-6001, TPX-7001, artenimol, andAMG-592, or a pharmaceutically acceptable salt of any of the foregoing,or any combination thereof.

Psoriasis Combination Therapy

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents that are useful for treating orameliorating psoriasis. In some embodiments, the compounds providedherein, or pharmaceutically acceptable salts thereof, may be combinedwith one, two, three, or four additional therapeutic agents selectedfrom acetaldehyde dehydrogenase inhibitor, adenosine A1 receptorantagonist, adenosine A3 receptor antagonist, adenosine A3 receptoragonists, ADP ribosyl cyclase-1 inhibitors, alpha 2 adrenoceptormodulator, apolipoprotein A antagonist, aryl hydrocarbon receptoragonist, Bcl-xL Bcl-2 associated death promotor modulators, beta amyloidantagonist, beta-catenin inhibitors, bromodomain containing proteininhibitor, Ca2+ release activated Ca2+ channel 1 inhibitors, calcineurininhibitors, calcium channel inhibitors, cannabinoid CB1 receptorantagonist, cathepsin S inhibitors, CCR3 chemokine antagonists, CXCR2chemokine antagonist, CXCR1/2 chemokine, CCR6 chemokine antagonist,CD223 modulators, CD40 ligand receptor antagonists, cell adhesionmolecule inhibitors, cell surface glycoprotein MUC18 inhibitors, CREBbinding protein inhibitors, CXCR4 chemokine modulators, cytokinereceptor antagonist, cytosolic phospholipase A2 inhibitors, DHFRinhibitors, DYRK-1 alpha protein kinase inhibitor, EGFR family tyrosinekinase receptor inhibitors, enolase 1 inhibitor, eotaxin ligandinhibitors, FIFO ATP synthase modulator, free fatty acid receptor 2agonist, free fatty acid receptor 3 agonist, galectin-3 inhibitors,glucocorticoid agonists, GM-CSF ligand inhibitors, GNRH receptormodulators, 5-HT 1a receptor antagonist, FGF receptor antagonist, GroELprotein 2 inhibitor, histamine H1 receptor antagonists, histamine H4receptor antagonists, histone deacetylase-1 inhibitors, histonedeacetylase-2 inhibitors, histone deacetylase-3 inhibitors, histonedeacetylase-6 inhibitors, Hsp 90 inhibitor, IL-1 receptor antagonist,interleukin 1 like receptor 2 inhibitor, IL-2 receptor alpha subunitstimulator, IL-2 modulator, IL-10 antagonists, IL-12 antagonists, IL-17agonist, IL17RA gene inhibitor, IL-17 antagonists, IL-23 antagonists,IL-8 antagonists, immunoglobulin like domain receptor 2 antagonist,insulin receptor substrate-1 inhibitors, interferon gamma receptorantagonists, interleukin 17 ligand inhibitors, interleukin 17A ligandinhibitors, interleukin 17A ligand modulators, interleukin 17F ligandinhibitors, interleukin 23A inhibitors, interleukin receptor 17Aantagonists, interleukin receptor 17A modulators, interleukin-1 alphaligand inhibitors, interleukin-1 beta ligand modulators, IRAK-4 proteinkinase inhibitor, Itk tyrosine kinase inhibitor, JAK tyrosine kinaseinhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinaseinhibitors, Jak3 tyrosine kinase inhibitors, KCNA voltage-gatedpotassium channel-3 inhibitors, Lck tyrosine kinase inhibitors,lysophosphatidate-1 receptor antagonists, MALT protein 1 inhibitors, MAPkinase inhibitors, membrane copper amine oxidase inhibitors,metalloprotease-1 inhibitors, mitochondrial 10 kDa heat shock proteinstimulators, mTOR complex 1 inhibitor, mTOR complex 2 inhibitor, nonreceptor tyrosine kinase TYK2 antagonists, nuclear erythroid 2-relatedfactor 2 stimulators, nuclear factor kappa B inhibitors, nucleosidereverse transcriptase inhibitors, oncostatin M receptor subunit betainhibitor, opioid receptor delta antagonists, OX40 ligand inhibitor,parathyroid hormone ligand inhibitors, PDE 4 inhibitors, PDE 4binhibitor, P2Y6 purinoceptor modulator; P-glycoprotein inhibitors,phosphoinositide-3 kinase delta inhibitors, phosphoinositide-3 kinasegamma inhibitors, phospholipase A2 inhibitors, programmed cell deathligand 1 modulators, programmed cell death protein 1 stimulator,P-selectin glycoprotein ligand-1 stimulators, retinoic acid receptoragonists, retinoic acid receptor gamma antagonists, retinoic acidreceptor gamma inverse agonists, retinoid receptor agonists, retinoid Xreceptor agonists, retinoid X receptor modulators, retinoid Z receptorgamma agonists, retinoid Z receptor gamma inverse agonists, retinoid Zreceptor gamma antagonist, rho associated protein kinase 2 inhibitors,ribonuclease P inhibitors, RIP-1 kinase inhibitor,sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphatereceptor-1 modulators, Src tyrosine kinase inhibitors, STAT-3inhibitors, Syk tyrosine kinase inhibitor, T-box transcription factorTBX21 modulators, T-cell differentiation antigen CD6 inhibitors, T-cellsurface glycoprotein CD8 inhibitors, T cell surface glycoprotein CD28stimulator, TGF beta agonists, TLR-7 antagonists, TLR-8 antagonists,TLR-9 antagonists, TNF alpha ligand inhibitors, TNF alpha ligandmodulators, TNF antagonists, TNF binding agents, TNF gene inhibitor,topoisomerase II inhibitors, TrkA receptor antagonists, tubulin bindingagents, Tyk2 tyrosine kinase inhibitor, type II TNF receptor modulators,unspecified cytokine receptor antagonists, vitamin D3 receptor agonists,vitamin D3 receptor modulators, Wnt ligand inhibitor, and Wnt 5A ligandinhibitor.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents selected from AP-005, 18C3 (anti-IL-1alpha true human antibody), ABX-464, acitretin, adalimumab, adipocell,AFB-035, aganirsen, AKP-11, alefacept, alitretinoin, Amilo-5mer,aminopterin, amiselimod, apremilast, ASKP-1240, AST-005, ATI-2138,AVX-001, baricitinib, belapectin (GR-MD-02), bertilimumab,betamethasone, BI-655066, BI-730357, BI-730460, BI-730460, bimekizumab,BMS-986165, BMX-010, briakinumab, brodalumab, BTT-1023, C-82,calcipotriol, calcitriol, CC-90005, CCL-20LD, CD-10367, certolizumabpegol, CF-101, ciclosporin, CJM-112, CKBA, clobetasolpropionate+tretinoin, CM-2489, CPL-409116, crisaborole, CS-12192,CT-327, CTX-101, dalazatide, DFD-06, dimethyl fumarate, dithranol,DLX-105, DSXS-1411, DSXS-1535, DUR-928, EDP-1815, etanercept,fluocinonide, FPP-003, GK-664-S, GLG-801, GLPG-3121, GLPG-3667,GLPG-3970, GLY-2028, GMDP, GSK-2800528, GSK-2831781, GSK-2981278A,guselkumab, halomethasone, HAT-1, IMO-3100, IMO-8400, inecalcitol,infliximab, INV-103, IR-444, IR-502, itolizumab, ixekizumab, JN-2528,KBL-697, KD-025, LAS-41004, LEO-124249, LEO-29102, LEO-32731, LEO-35299,lithium succinate, LNP-1955, LP-0200, M-1095, maxacalcitol, MDX-018,methotrexate, MOL-4249, mometasone, MP-1032, MSB-03, myristylnicotinate, namilumab, neihulizumab, niclosamide, NLP-91, NP-000888,NVN-1000, olopatadine, orilotimod, P-3072, P-3073, PAT-1657, Pc4,pefcalcitol, PF-06700841, Prurisol, PRX-003, PRX-167700, PUR-0110,recombinant human LFA-3/antibody fusion protein, RON-2315, RTU-1096,5-414114, secukinumab, SHP-141, SMET-D1, SNK-01, SP-14019, SSS-07,tacalcitol, tazarotene, tildrakizumab, tirbanibulin (KX-01),tofacitinib, toreforant, tregalizumab, TU-2100, UCB-5857, UHE-105,ulobetasol, ustekinumab, VBY-891, voclosporin, VTP-43742, WBI-1001, andZPL-389, or a pharmaceutically acceptable salt of any of the foregoing,or any combination thereof.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents selected from:

-   -   acetaldehyde dehydrogenase inhibitor, including but not limited        to ADX-629;    -   adenosine A3 receptor agonists, including but not limited to        piclidenoson (CF-101);    -   adenosine A3 receptor antagonist, including but not limited to        PBF-1650;    -   ADP ribosyl cyclase-1 inhibitors, including but not limited to        IMO-3100;    -   5-HT 1a receptor antagonist, including but not limited to        AX-1602;    -   apolipoprotein A antagonist, including but not limited to        orticumab;    -   cytokine receptor antagonist, including but not limited to        tapinarof;    -   aryl hydrocarbon receptor modulator, including but not limited        to NTI-528 and RLV-102;    -   Bcl-xL Bcl-2 associated death promotor modulators, including but        not limited to Pc4;    -   beta-catenin inhibitors, including but not limited to C-82;    -   bromodomain containing protein inhibitor, including but not        limited to BOS-475;    -   Ca2+ release activated Ca2+ channel 1 inhibitors, including but        not limited to CM-2489 and PRCL-02;    -   calcineurin inhibitors, including but not limited to        voclosporin, pimecrolimus, tacrolimus, ciclosporin, HS-378,        oxeclosporin, OLO-400, ADV-P3, and CTX-006;    -   calcium channel inhibitors, including but not limited to        RP-3128;    -   cathepsin S inhibitors, including but not limited to VBY-129,        VBY-891, RWJ-445380, and CRA-028129;    -   CCR3 chemokine antagonists, including but not limited to        bertilimumab;    -   CXCR2 chemokine antagonist, including but not limited to        CCX-624;    -   CD223 modulators, including but not limited to GSK-2831781;    -   CD40 ligand receptor antagonists, including but not limited to        ASKP-1240, lucatumumab, and toralizumab;    -   cell adhesion molecule inhibitors, including but not limited to        BIRT-2584, PC-114, alicaforsen, IC-747, ICM-3, and ISIS-2302;    -   cell surface glycoprotein MUC18 inhibitors, including but not        limited to PRX-003 and imaprelimab;    -   CREB binding protein inhibitors, including but not limited to        C-82;    -   CXCR1/2 chemokine, including but not limited to LY-3041658;    -   CXCR4 chemokine modulators, including but not limited to        CD184-FK506 ADC;    -   cytosolic phospholipase A2 inhibitors, including but not limited        to AVX-001;    -   DHFR inhibitors, including but not limited to methotrexate,        CH-4051, CePep, CH-1504, MQX-5902, and MPI-2505;    -   DYRK-1 alpha protein kinase inhibitor, including but not limited        to VRN-02;    -   EGFR family tyrosine kinase receptor inhibitors, including but        not limited to erlotinib, icotinib hydrochloride, and SGT-210;    -   Enolase 1 inhibitor, including but not limited to HuL-001;    -   Eotaxin ligand inhibitors, including but not limited to        bertilimumab;    -   FIFO ATP synthase modulator, including but not limited to        LYC-30937;    -   FGF receptor antagonist, including but not limited to potassium        dobesilate;    -   free fatty acid receptor 2, 3 agonist, including but not limited        to SFA-002;    -   galectin-3 inhibitors, including but not limited to belapectin        (GR-MD-02);    -   glucocorticoid agonists, including but not limited to        betamethasone, clobetasol, auranofin, NM-135, DSXS-1538b, and        SEGRA;    -   GM-CSF ligand inhibitors, including but not limited to        namilumab;    -   GNRH receptor modulators, including but not limited to NL-001;    -   GroEL protein 2 inhibitor, including but not limited to        prozumab;    -   histamine H1 receptor antagonists, including but not limited to        olopatadine and loratadine+nortriptyline;    -   histamine H4 receptor antagonists, including but not limited to        toreforant and ZPL-389;    -   histone deacetylase-2 inhibitors, including but not limited to        KAR-1880;    -   histone deacetylase 1, 6, 2, 3 inhibitors, including but not        limited to remetinostat (SHP-141);    -   Hsp 90 inhibitor, including but not limited to CTXT-102;    -   IL-2 receptor alpha subunit stimulator, including but not        limited to NKTR-358;    -   IL-2 modulator; including but not limited to CC-92252;    -   IL-10 antagonists, including but not limited to pimecrolimus;    -   IL-12 antagonists, including but not limited to BOW-090,        briakinumab, FM-202, and apilimod;    -   IL-17 antagonists, including but not limited to ixekizumab,        secukinumab, AFB-035, KD-025, DLX-3003, EBI-028, M-1095,        IMO-3100, GR-1501, 608, vunakizumab, sonelokimab, AK-111,        HB-0017, and SIM-335;    -   IL-17 agonist, including but not limited to ZL-1102;    -   IL17RA gene inhibitor, including but not limited to XCUR-17;    -   IL-23 antagonists, including but not limited to tildrakizumab,        BI-655066, AMG-139, briakinumab, mirikizumab (LY-3074828), F        M-202, apilimod, LY-2525623, risankizumab, and IBI-112;    -   IL-23 antagonist, including but not limited to ustekinumab and        AK-101;    -   IL-8 antagonists, including but not limited to BMS-986253        (MDX-018), A S-101, ABX-IL8, LI-312, SB-332235, and LF-216;    -   immunoglobulin like domain receptor 2 antagonist, including but        not limited to CGEN-15001;    -   insulin receptor substrate-1 inhibitors, including but not        limited to aganirsen;    -   interferon gamma receptor antagonists, including but not limited        to pimecrolimus, AMG-811, OA-1, AGT-1, mometasone+nortriptyline,        and fontolizumab;    -   interleukin 17 ligand inhibitors, including but not limited to        CJM-112, netakimab, and AFB-035;    -   interleukin 17A ligand inhibitors, including but not limited to        COVA-322, JS-005, and ABY-035/AFO2;    -   interleukin 17A ligand modulators, including but not limited to        QX-002-N;    -   interleukin 17A/17F ligand inhibitors, including but not limited        to bimekizumab;    -   interleukin 23A inhibitors, including but not limited to        guselkumab and QX-004-N;    -   interleukin receptor 17A antagonists, including but not limited        to brodalumab and LZM-012;    -   interleukin 1 like receptor 2 inhibitor, including but not        limited to spesolimab and imsidolimab;    -   interleukin-1 alpha ligand inhibitors, including but not limited        to bermekimab (CA-18C3);    -   interleukin-1 beta ligand modulators, including but not limited        to PUR-0110 and AR-100;    -   IRAK-4 protein kinase inhibitor, including but not limited to        BAY-1834845;    -   Itk tyrosine kinase inhibitor, including but not limited to        JTE-051;    -   JAK tyrosine kinase inhibitors, including but not limited to        CS-17380;    -   Jak1 tyrosine kinase inhibitors, including but not limited to        itacitinib, abrocitinib (PF-04965842), solcitinib, SHR-0302, and        filgotinib;    -   JAK1,2,3 tyrosine kinase inhibitor, including but not limited to        jaktinib;    -   JAk1,2 tyrosine kinase inhibitor, including but not limited to        baricitinib and ruxolitinib;    -   TYk2 tyrosine kinase inhibitor, including but not limited to        brepocitinib;    -   Jak1 tyrosine kinase inhibitor, including but not limited to        PF-06263276;    -   JAk 1, 3 tyrosine kinase inhibitor, including but not limited to        CS-944X, tofacitinib, and peficitinib;    -   KCNA voltage-gated potassium channel-3 inhibitors, including but        not limited to KPI-150, dalazatide, BNC-164, and SPS-4251;    -   Lck tyrosine kinase inhibitors, including but not limited to        BMS-350751 and NTRC-0625-0;    -   lysophosphatidate-1 receptor antagonists, including but not        limited to BMS-986202;    -   MAP kinase inhibitors, including but not limited to AIK-33 and        KIN-3032;    -   membrane copper amine oxidase inhibitors, including but not        limited to vepalimomab, BTT-1023, RTU-1096, and PRX-167700;    -   metalloprotease-1 inhibitors, including but not limited to        KIN-3032 and HMR-1571;    -   mitochondrial 10 kDa heat shock protein stimulators, including        but not limited to INV-103;    -   Non receptor tyrosine kinase TYK2 antagonists, including but not        limited to SAR-20347, ICP-332, and SDC-1801;    -   nuclear erythroid 2-related factor 2 stimulators, including but        not limited to dimethyl fumarate and XP-23829;    -   nuclear factor kappa B inhibitors, including but not limited to        S-414114, VGX-1027, AKBA, SP-100030, and YP-008;    -   nucleoside reverse transcriptase inhibitors, including but not        limited to Prurisol;    -   oncostatin M receptor subunit beta inhibitor, including but not        limited to vixarelimab;    -   Opioid receptor delta antagonists, including but not limited to        HS-378;    -   OX40 ligand inhibitor, including but not limited to KY-1005;    -   P38 MAP kinase inhibitor, including but not limited to AMG-101,        AIK-3, VGX-1027, AIK-al, BMS-582949, doramapimod, semapimod,        TA-5493, HEP-689, and RWJ-68354;    -   parathyroid hormone ligand inhibitors, including but not limited        to inecalcitol;    -   PDE 4 inhibitors, including but not limited to apremilast,        roflumilast, orismilast, MK-0873, Ro-20-1724, HMR-1571,        RPR-122818, HPP-737, crisaborole, and DC-591042;    -   PDE 4b inhibitor, including but not limited to GRT-6015;    -   TNF alpha ligand inhibitor, including but not limited to        Hemay-005;    -   P-Glycoprotein inhibitors, including but not limited to        boningmycin;    -   Beta amyloid antagonist, including but not limited to GC-021109;    -   phosphoinositide-3 kinase delta inhibitors, including but not        limited to seletalisib (UCB-5857);    -   mTOR complex 2 inhibitor, including but not limited to        bimiralisib;    -   phosphoinositide-3 kinase gamma inhibitors, including but not        limited to TAT-N25 peptide;    -   phospholipase A2 inhibitor, including but not limited to        ZPL-521, Project P-0229, BMS-181162, and BMS-188184;    -   programmed cell death ligand 1 modulators, including but not        limited to GX-P2;    -   programmed cell death protein 1 stimulator, including but not        limited to LY-3462817 and CC-90006;    -   P-selectin glycoprotein ligand-1 stimulators, including but not        limited toneihulizumab;    -   P-selectin glycoprotein ligand-1, including but not limited to        AbGn-168H;    -   retinoic acid receptor agonists, including but not limited to        acitretin, tazarotene, tretinoin, tazarotene arotinoid        trometamol, CD-1599, AM-580, BMS-181163, and CPR-2005;    -   retinoic acid receptor gamma antagonists, including but not        limited to VTP-43742 and BBI-6000;    -   retinoic acid receptor gamma inverse agonists, including but not        limited to GSK-2981278A and JNJ-3534;    -   retinoid receptor agonists, including but not limited to RASP;    -   retinoid X receptor agonists, including but not limited to        LGD-1550;    -   retinoid X receptor modulators, including but not limited to        bexarotene, alitretinoin, ALRT-1069, LGD-1069, and Net-41B;    -   retinoid Z receptor gamma agonists, including but not limited to        NCE-407;    -   retinoid Z receptor gamma inverse agonists, including but not        limited to ARN-6039, IMU-935, BOS-172767, SAR-441169, and        INV-17;    -   retinoid Z receptor gamma antagonist, including but not limited        to AUR-101, JTE-451, ESR-114, ABBV-157, and AZD-0284;    -   rho associated protein kinase 2 inhibitors, including but not        limited to KD-025;    -   RIP-1 kinase inhibitor, including but not limited to        GSK-2982772, DNL-758, and VRN-04;    -   ribonuclease P inhibitors, including but not limited to RASP;    -   sphingosine-1-phosphate receptor-1 modulators, including but not        limited to amiselimod, AKP-11, FP-253, and CS-0777;    -   sphingosine-1-phosphate receptor-1 agonist, including but not        limited to AK-119, SCD-044, and SYL-927;    -   sphingosine-1-phosphate receptor-5 modulator, including but not        limited to CBP-307;    -   Src tyrosine kinase inhibitors, including but not limited to        tirbanibulin (KX-01);    -   STAT-3 inhibitors, including but not limited to TAK-114,        GLG-801, and MOL-4249;    -   Syk tyrosine kinase inhibitor, including but not limited to        HMPL-523;    -   T-box transcription factor TBX21 modulators, including but not        limited to SB-020;    -   T-cell differentiation antigen CD6 inhibitors, including but not        limited to itolizumab;    -   T-cell surface glycoprotein CD8 inhibitors, including but not        limited to tregalizumab;    -   T cell surface glycoprotein CD28 stimulator, including but not        limited to theralizumab;    -   TGF beta agonists, including but not limited to tregalizumab;    -   TLR-7 antagonists, including but not limited to IMO-3100;    -   TLR-9 antagonists, including but not limited to IMO-3100 and        GNKS-356;    -   TLR 7,8,9 antagonist, including but not limited to IMO-8400;    -   TNF alpha ligand inhibitors, including but not limited to        adalimumab, CHS-1420, BAX-2923, MSB-11022, ABP-501, MYL-1401A,        infliximab, certolizumab pegol, AST-005, etanercept, opinercept,        ISIS-104838, DLX-105, SSS-07, DLX-2751, DLX-105, Debio-0512,        TAQ-588, adalimumab, placulumab, PMI-001, CYT-020-TNFQb,        AN-0128, CYT-007-TNFQb, SYI-2074, YP-008, SCT-640A, SBT-104, and        T-1649;    -   TNF alpha ligand modulators, including but not limited to        PUR-0110, CDP-571, and ACU-D2;    -   TNF antagonists, including but not limited to certolizumab        pegol, SCB-808, BAX-2200, CT-P05, SCB-131, GSK-2800528,        onercept, and ALS-00T2-0501;    -   TNF binding agents, including but not limited to adalimumab,        certolizumab pegol SCB-131, onercept, CT-P17, SBC-808, ABP-501,        MYL-1401A, MSB-11022, BAX-2923, CHS-1420, and BCD-057;    -   TNF gene inhibitor, including but not limited to AST-005;    -   topoisomerase II inhibitors, including but not limited to        GPX-150;    -   TrkA receptor antagonists, including but not limited to VM-902A,        CT-327, K-252a, and lestaurtinib;    -   tubulin binding agents, including but not limited to KX-01 and        paclitaxel;    -   Tyk2 tyrosine kinase inhibitor, including but not limited to        deucravacitinib, PF-06826647, ABBV-712, and CS-43001;    -   type II TNF receptor modulators, including but not limited to        TNR-001, BAX-2200, and SCB-131;    -   unspecified cytokine receptor antagonists, including but not        limited to tetrathiomolybdate, JD-4000, X-083-NAB, SPHD-400,        pimecrolimus, and HMPL-010;    -   vitamin D3 receptor agonists, including but not limited to        inecalcitol, maxacalcitol, calcipotriol, falecalcitriol,        maxacalcitol, calcitriol NS-78, tacalcitol, calcipotriol,        calcithiazol, ecalcidene, lexacalcitol, atocalcitol, and        Ro-65-2299;    -   vitamin D, D3 receptor modulators, including but not limited to        VS-320 and VS-105;    -   Wnt ligand inhibitor, including but not limited to SM-04755; and    -   Wnt 5A ligand inhibitor, including but not limited to Box-5.

Rheumatoid Arthritis Combination Therapy

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents that are useful for treating orameliorating rheumatoid arthritis. In some embodiments, the compoundsprovided herein, or pharmaceutically acceptable salts thereof, may becombined with one, two, three, or four additional therapeutic agentsselected from 14-3-3 protein eta inhibitors, 5-lipoxygenase inhibitors,abl tyrosine kinase inhibitors, ACTH receptor agonists, adenosine A3receptor agonists, adenosine deaminase inhibitors, ADP ribosyl cyclase-1inhibitors, ADP ribosyl cyclase-1 modulators, ADP ribosylation factor 6inhibitors, adrenocorticotrophic hormone ligands, aggrecanase-2inhibitors, albumin modulators, anti-TNF steroid conjugate, adenosine A1receptor antagonist, annexin A1 modulator, AP1 transcription factorinhibitors, apolipoprotein B modulator, aryl hydrocarbon receptoragonist plus autoantigen, basigin inhibitors, bcr protein inhibitors,B-lymphocyte antigen CD19 inhibitors, B-lymphocyte antigen CD20inhibitors, B-lymphocyte antigen CD20 modulators, B-lymphocyte celladhesion molecule inhibitor, B-lymphocyte stimulator ligand inhibitors,bradykinin receptor modulators, BRAF gene inhibitors, branched aminoacid aminotransferase 1 inhibitors, bromodomain containing proteininhibitors, Btk tyrosine kinase inhibitors, cadherin-11 antagonists,calcineurin inhibitors, calcium channel inhibitors, calreticulininhibitor, carbonic anhydrase inhibitors, cathepsin K inhibitors,cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2 chemokineantagonists, CCR3 gene modulators, CCR5 chemokine antagonists, CD126antagonists, CD29 modulators, CD3 modulators, CD39 agonists, CD4agonists, CD4 antagonists, CD40 ligand inhibitors, CD40 ligand receptorantagonists, CD40 ligand receptor modulators, CD52 antagonists, CD73agonists, CD79b modulators, CD80 antagonists, CD86 antagonists, CD95antagonists, cell adhesion molecule inhibitors, chaperonin modulator,choline kinase inhibitors, clusterin stimulators, complement C5 factorinhibitors, complement factor stimulators, C-reactive proteininhibitors, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR4chemokine antagonists, cyclin-dependent kinase inhibitor 1 inhibitors,cyclin-dependent kinase-2 inhibitors, cyclin-dependent kinase-4inhibitors, cyclin-dependent kinase-5 inhibitors, cyclin-dependentkinase-6 inhibitors, cyclin-dependent kinase-7 inhibitors,cyclin-dependent kinase-9 inhibitors, cyclooxygenase 2 inhibitors,cyclooxygenase 2 modulators, cyclooxygenase inhibitors, cytosolicphospholipase A2 inhibitors, cytotoxic T-lymphocyte protein-4modulators, cytotoxic T-lymphocyte protein-4 stimulators,deoxyribonuclease gamma stimulator, DHFR inhibitors, diamineacetyltransferase inhibitors, dihydroorotate dehydrogenase inhibitors,DYRK-1 alpha protein kinase inhibitor, elongation factor 2 inhibitors,enolase 1 inhibitor, eotaxin 2 ligand inhibitors, EP4 prostanoidreceptor antagonists, erythropoietin receptor agonists, factor XIIaantagonist, Fas ligands, FGF-2 ligand inhibitors, FK506 bindingprotein-12 modulators, folate antagonists, folate receptor agonists,folate receptor beta antagonists, folate receptor modulators,fractalkine ligand inhibitors, fyn tyrosine kinase inhibitors, G proteincoupled receptor 15 antagonists, GABA A receptor modulators,glucocorticoid agonists, glucocorticoid antagonists, glucocorticoidinduced leucine zipper stimulators, GM-CSF ligand inhibitors, GM-CSFreceptor antagonists, GM-CSF receptor modulators, growth regulatedprotein alpha ligand inhibitors, H+K+ ATPase inhibitors, histamine H4receptor antagonists, histone deacetylase inhibitors, histonedeacetylase-6 inhibitors, HIV-1 gp120 protein inhibitors, HLA class IIantigen DQ-2 alpha modulators, HLA class II antigen inhibitors, HLAclass II antigen modulators, Hsp 70 family inhibitors, hypoxia induciblefactor-1 inhibitors, IFNB gene stimulators, I-kappa B kinase betainhibitors, I-kappa B kinase inhibitors, IL-1 antagonists, IL-10agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17antagonists, IL-17 receptor modulators, IL-18 receptor accessory proteinantagonist, IL-8 ligand inhibitors, IL-2 agonists, IL-2 antagonists,IL-21 antagonists, IL-23 antagonists, IL-3 antagonists, IL-4 agonists,IL-6 antagonists, IL-6 receptor modulators, IL-6 neutralizing humanantibodies, anti-IL6 antibody, immunoglobulin antagonists,immunoglobulin G1 agonists, immunoglobulin G1 antagonists,immunoglobulin G1 modulators, immunoglobulin G2 antagonists,immunoglobulin G2 modulators, immunoglobulin gamma Fc receptor IImodulators, immunoglobulin gamma Fc receptor IIB antagonists,immunoglobulin kappa modulators, immunoglobulin M antagonists, induciblenitric oxide synthase inhibitors (iNOS inhibitors), inosinemonophosphate dehydrogenase inhibitors, insulin sensitizers, integrinalpha-1/beta-1 antagonists, integrin alpha-4/beta-1 antagonists,integrin alpha-9 antagonist, integrin antagonists, interferon betaligands, interferon gamma ligands, interleukin 17A ligand inhibitors,interleukin 17F ligand inhibitors, interleukin 23A inhibitors,interleukin ligands, interleukin receptor 17A antagonists, interleukin-1beta ligand inhibitors, interleukin-10 ligands, interleukin-2 ligands,interleukin-4 ligands, Interleukin-6 ligand inhibitors, Itk tyrosinekinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinaseinhibitors, Jak2 tyrosine kinase inhibitors, JAK3 gene inhibitors, Jak3tyrosine kinase inhibitors, Jun N terminal kinase inhibitors, KCNAvoltage-gated potassium channel-3 modulators, kelch like ECH associatedprotein 1 modulators, kit tyrosine kinase inhibitors, LanC like protein2 modulators, leukotriene BLT receptor antagonist, LITAF geneinhibitors, lymphocyte function antigen-3 receptor antagonists, Lyntyrosine kinase inhibitors, macrophage-drug conjugate (MDC), macrophagemannose receptor 1 modulators, MAdCAM inhibitors, MAP kinase modulators,MAP3K2 gene inhibitors, MAPKAPK5 inhibitors, matrix metalloproteaseinhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1protein kinase inhibitors, MEK-2 protein kinase inhibitors, membranecopper amine oxidase inhibitors, metalloprotease-2 inhibitors,metalloprotease-9 inhibitors, methylprednisolone, midkine ligandinhibitors, mitochondrial 10 kDa heat shock protein stimulators, mTORcomplex 1 inhibitors, mTOR inhibitors, NAD ADP ribosyltransferasestimulators, NAMPT gene inhibitors, NF kappa B inhibitor stimulators,NFAT gene inhibitors, NFE2L2 gene stimulators, nicotinic acetylcholinereceptor antagonists, NK cell receptor modulators, NKG2 A B activatingNK receptor antagonists, NKG2 D activating NK receptor antagonists,nuclear erythroid 2-related factor 2 stimulators, nuclear factor kappa Binhibitors, nuclear factor kappa B modulators, nuclear factor kappa Bp105 inhibitors, opioid growth factor receptor agonists, opioid receptordelta antagonists, osteoclast differentiation factor antagonists,osteoclast differentiation factor ligand inhibitors, oxidoreductaseinhibitors, P2X7 purinoceptor agonists, p38 MAP kinase alpha inhibitors,p38 MAP kinase inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGFreceptor agonists, PDGF receptor antagonists, PDGF-B ligand inhibitors,PERK gene inhibitors, phosphoinositide-3 kinase delta inhibitors,phosphoinositide-3 kinase gamma inhibitors, phospholipase A2 inhibitors,platelet activating factor receptor antagonists, PPAR gamma agonists,programmed cell death protein 1 modulators, prostaglandin D synthasestimulators, protein arginine deiminase inhibitors, protein tyrosinekinase inhibitors, protease-activated receptor-2 antagonist, PurH purinebiosynthesis protein inhibitors, rho associated protein kinase 2inhibitors, seprase inhibitors, signal transducer CD24 modulators,signal transduction inhibitors, sodium glucose transporter-2 inhibitors,sphingosine 1 phosphate phosphatase modulators, STAT3 gene inhibitors,serum amyloid A protein modulator, superoxide dismutase stimulators, SYKfamily tyrosine kinase inhibitors, Syk tyrosine kinase inhibitors,syndecan-1 inhibitors, T cell receptor antagonists, T cell receptormodulators, T cell surface glycoprotein CD28 inhibitors, T cell surfaceglycoprotein CD28 stimulators, TAK1 binding protein modulators, talinmodulators, T-cell differentiation antigen CD6 inhibitors, T-cellsurface glycoprotein CD8 inhibitors, tenascin modulators, TGF betaagonists, thymulin agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-9antagonists, TNF alpha ligand inhibitors, TNF alpha ligand modulators,TNF antagonists, TNF gene inhibitors, TNF receptor modulators, TNFSF11gene inhibitors, transcription factor p65 inhibitors, transcriptionfactor RelB inhibitors, transferrin modulators, transthyretin modulator,tumor necrosis factor 13C receptor antagonists, tumor necrosis factor 15ligand inhibitors, tumor necrosis factor ligand 13 inhibitors, tumornecrosis factor ligand inhibitors, type I IL-1 receptor antagonists,type I TNF receptor antagonists, type II TNF receptor modulators,unspecified GPCR agonists, VEGF receptor antagonists, VEGF-2 receptorantagonists, VEGF-2 receptor modulators, VEGF-B ligand inhibitors,X-linked inhibitor of apoptosis protein inhibitors, and zap70 tyrosinekinase inhibitors.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents selected from 99mTc labelled annexinV-128, abatacept, abatacept biosimilar, ABBV-257, ABT-122, ABT-494,acalabrutinib, aceclofenac, actarit, AdMSCs, MS-392, adalimumab,adalimumab biosimilar, adalimumab follow-on biologic, AK-106, ALX-0061,Amilo-5MER, aminopterin, AMT-101, anakinra, anakinra biosimilar,anakinra follow-on biologic, annexuzlimab, ARG-301, ARQ-250, ASLAN-003,ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064, bimekizumab, BiP(rheumatoid arthritis), BLHP-006, blisibimod, BMS-986104, BMS-986142,ABBV-105, BTT-1023, canakinumab, Cartistem, CCX-354, CD24-IgFc,celecoxib, cerdulatinib, certolizumab pegol, CF-101, CFZ-533, CHR-5154,cibinetide, ciclosporin, clazakizumab, CNTO-6785, corticotropin,CR-6086, CreaVax-RA, CWG-92, CWG-940, Cx-611, DE-098, DEN-181,deflazacort, Rheumavax, denosumab, diacerein, diclofenac, DWJ-1421,E-6011, eicosapentaenoic acid monoglycerides, etanercept, etanerceptbiosimilar, etanercept follow-on biologic, etodolac, etoricoxib,filgotinib, fosdagrocorat, GLPG-3970, gerilimzumab, ginsenoside C-K,givinostat, GLPG-4399, goat polyclonal antibodies, golimumab, GS-5745,GS-9876, GSK-3196165, HHT-109, HM-71224, HMPL-523, HST-003, hyaluronatesodium, (S)-hydroxychloroquine, IB-RA (injectable, rheumatoidarthritis), IB-RA (oral, rheumatoid arthritis), IcanoMAB, ICP-022,iguratimod, IMD-2560, imidazole salicylate, infliximab, infliximabbiobetter, infliximab biosimilar, CT-P13, INSIX RA, interferon gammafollow-on biologic, interleukin-2 (injectable), interleukin-2 follow-onbiologic, INV-103, IR-501, itolizumab, JNJ-40346527, Ka Shu Ning,KB-312, KD-025, ketoprofen+omeprazole, KINE-101, LB-600, leflunomide,lenzilumab, LLDT-8, LNK-01001, LNP-1955, lumiracoxib, LY-3090106,masitinib, mavrilimumab, MBS-2320, MEDI-5117, meloxicam, methotrexate,MGD-010, misoprostol+diclofenac, MM-A01-01, monalizumab, MORAb-022,MPC-300-IV, MRC-375, nabumetone, namilumab, naproxen+esomeprazole,naproxen+esomeprazole strontium, NIP-046, ocaratuzumab, ofatumumab,OHR-118, olokizumab, OM-89, once-daily naproxen (oral controlledrelease, pain), ONO-4059, Oralgam, ozoralizumab, PAR-2 inhibitors,peficitinib, pelubiprofen, PF-06687234, piperidone hydrochloridum,piroxicam, prednisolone, prednisone, Procell, Prosorba, PRT-2607,PRTX-100, PRX-167700, QBSAU, rabeximod, RCT-18, recombinant human CD22monoclonal antibody (iv infusion), Lonn Ryonn Pharma/SinoMab Bioscience(Shenzhen), RA-Curcusome, recombinant human interleukin-1 receptorantagonist (rheumatoid arthritis), recombinant human interleukin-2recombinant TNF receptor 2-Fc fusion protein mutant, RG-6125, RhuDex,rifabutin+clarithromycin+clofazimine, rituximab, rituximab biosimilar,Toritz, rituximab follow-on biologic, RPI-78, SAN-300, sarilumab,SBI-087, seliciclib, SHR-0302, sirukumab, spebrutinib, SR-047, SSS-07,KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079,tarenflurbil (transdermal spraygel, skin disease/rheumatoid arthritis),technetium Tc 99m tilmanocept, technetium[99Tc] methylenediphosphonate,tenoxicam, Debio-0512, tocilizumab, tofacitinib, tofacitinib citrate,TQG-2813, Trichuris suis ova, umbilical cord-derived mesenchymal stemcells (iv, RA/liver disease), ustekinumab, VAY-736, VB-201, WF-10,XmAb-5871, YH-1713, YHB-1411-2, YRA-1909, and ZM-008, or apharmaceutically acceptable salt of any of the foregoing, or anycombination thereof.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one, two, three, or fouradditional therapeutic agents selected from:

-   -   14-3-3 protein eta inhibitors, including but not limited to        anti-AGX-020 mAbs (rheumatoid arthritis) and Augurex;    -   5-Lipoxygenase inhibitors, including but not limited to        darbufelone, tebufelone, ZD-2138, etalocib, PGV-20229, L-708780,        T-0757, T-0799, ZM-216800, L-699333, BU-4601A, and SKF-104351;    -   5-Lipoxygenase/Cyclooxygenase inhibitors, including but not        limited to tenoxicam, licofelone, tenidap, tepoxalin, flobufen,        SKF-86002, WY-28342, and CI-986;    -   5-Lipoxygenase/PPAR gamma agonists, including but not limited to        etalocib;    -   Abl tyrosine kinase inhibitors/Bcr protein inhibitors/Kit        tyrosine kinase inhibitors/PDGF receptor antagonists/Signal        transduction inhibitors, including but not limited to imatinib;    -   ACTH receptor agonists/Adrenocorticotrophic hormone        ligands/Opioid growth factor receptor agonists, including but        not limited to FAR-404 and metenkefalin acetate+tridecactide        acetate;    -   adenosine A1 receptor antagonist, including but not limited to        CP-25;    -   adenosine A3 receptor agonists, including but not limited to        CF-101 (piclidenoson);    -   adenosine deaminase inhibitors, cladribine, pentostatin, and        FR-221647;    -   ADP ribosyl cyclase-1 inhibitors, including but not limited to        daratumumab;    -   ADP ribosyl cyclase-1 modulators/syndecan-1 inhibitors,        including but not limited to indatuximab ravtansine;    -   ADP ribosylation factor 6 inhibitors, including but not limited        to NAV-2729;    -   adrenocorticotrophic hormone ligands, including but not limited        to corticotropin and Mallinckrodt;    -   aggrecanase-2/TNF gene inhibitors, including but not limited to        GIBH-R-001-2;    -   albumin modulators, including but not limited to ONS-1210;    -   albumin modulators/IL-6 antagonists, including but not limited        to ALX-0061 (vobarilizumab);    -   albumin modulators/TNF alpha ligand inhibitors, including but        not limited to HOT-3010;    -   AP1 transcription factor/nuclear factor kappa B inhibitors,        including but not limited to tarenflurbil and SP-100030;    -   anti-TNF steroid antibody-drug conjugates (anti-TNF-GRM),        including but not limited to ABBV-3373 and ABBV-154;    -   basigin inhibitors/branched amino acid aminotransferase        1/metalloprotease-9 inhibitors/metalloprotease-2 inhibitors,        including but not limited to ERG-240;    -   BET inhibitors, including but not limited to GSK-3358699;    -   bispecific anti-CD86/IL-10, including but not limited to        APVO-210;    -   bispecific humanized monoclonal antibody targeted against BAFF        and IL-17A, including but not limited to tibulizumab;    -   bispecific antibody-peptide conjugate (BAFF/ICOSL), including        but not limited to AMG-570;    -   B-lymphocyte antigen CD19 inhibitors, including but not limited        to MDX-1342;    -   B-lymphocyte antigen CD19 inhibitors/immunoglobulin gamma Fc        receptor IIB antagonists, including but not limited to        XmAb-5871;    -   B-lymphocyte antigen CD20 inhibitors, including but not limited        to ocrelizumab, ofatumumab, rituximab, ABP-798, Maball, Mabtas,        Reditux, Zytux, veltuzumab, ocaratuzumab, BLX-301, IDEC-102,        ABP-798, GP-2013, MK-8808, HLX-01, CT-P10, TL-011, PF-05280586,        IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101, and        JHL-1101;    -   B-lymphocyte antigen CD20 modulators, including but not limited        to SBI-087, TRU-015, DXL-625, and MabionCD20;    -   B-lymphocyte cell adhesion molecule inhibitor, including but not        limited to SM-06;    -   B-lymphocyte stimulator ligand inhibitors, including but not        limited to belimumab, RCT-18, blisibimod, tabalumab, and        briobacept;    -   B-lymphocyte stimulator ligand/Tumor necrosis factor ligand 13        inhibitors, including but not limited to atacicept;    -   bradykinin receptor modulators/histone deacetylase        inhibitors/P2X7 purinoceptor agonists, including but not limited        to givinostat;    -   BRAF gene/MEK protein kinase/PERK gene inhibitors, including but        not limited to binimetinib;    -   Bromodomain containing protein inhibitors, including but not        limited to RVX-297, ZEN-003694    -   Btk tyrosine kinase inhibitors, including but not limited to        AC-0058, acalabrutinib, HM-71224, spebrutinib, BMS-986142,        TAK-020, tirabrutinib (ONO-4059), TAS-5315, ABBV-105, GDC-0834,        EBI-1459, BMS-986195, evobrutinib, fenebrutinib, SIMM-016, and        YZJ-3058;    -   Btk tyrosine kinase inhibitors/Syk tyrosine kinase        inhibitors/VEGF-2 receptor antagonists, including but not        limited to CG-026806;    -   Btk tyrosine kinase inhibitors/IL-6 antagonists, including but        not limited to RN-486;    -   Btk tyrosine kinase/Jak1 tyrosine kinase inhibitors, including        but not limited to upadacitinib+ABBV-105;    -   Btk tyrosine kinase/Jak3 tyrosine kinase inhibitors, including        but not limited to AC-0025;    -   cadherin-11 antagonists, including but not limited to RG-6125;    -   calcineurin inhibitors, including but not limited to        ciclosporin;    -   calcineurin inhibitors/opioid receptor delta antagonists,        including but not limited to HS-378;    -   calcium channel inhibitors, including but not limited to        RP-3128;    -   calreticulin inhibitor, including but not limited to ALB-001 and        ZYBK-2;    -   carbonic anhydrase/cyclooxygenase 2 inhibitors, including but        not limited to polmacoxib;    -   cathepsin K inhibitors, including but not limited to CRA-013783        and VEL-0230;    -   cathepsin K/cathepsin S inhibitors, including but not limited to        AM-3876 and NPI-2019;    -   cathepsin S inhibitors, including but not limited to MIV-247 and        RWJ-445380;    -   CCR1 chemokine antagonists, including but not limited to BX-471,        BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897, CP-481715,        and PS-375179;    -   CCR2 chemokine antagonists, including but not limited to MK-0812        and AZD-6942;    -   CCR3 gene modulators/eotaxin 2 ligand inhibitors, including but        not limited to CM-102;    -   CCR5 chemokine antagonists, including but not limited to        OHR-118, NIBR-6465, AZD-5672, and AZD-8566;    -   CD29 modulators/interleukin-10 ligands, including but not        limited to PF-06687234;    -   CD3 modulators, including but not limited to otelixizumab;    -   CD39/CD73 agonists, including but not limited to AAV5-CD39/CD73        (rheumatoid arthritis), and Arthrogen;    -   CCR5 chemokine antagonists/CD4 agonists/HIV-1 gp120 protein        inhibitors, including but not limited to maraviroc;    -   CD4 antagonists, including but not limited to zanolimumab,        MTRX-1011A, BW-4162W94, EP-1645, clenoliximab, and        DerG-PG275Cit;    -   CD40 ligand inhibitors, including but not limited to        dapirolizumab pegol, and TNX-1500;    -   CD40 ligand receptor antagonists, including but not limited to        BI-655064, anti-CD40-XTEN, teneliximab, VIB-4920, and iscalimab;    -   CD40 ligand receptor modulators/immunoglobulin G1 modulators,        including but not limited to CFZ-533;    -   CD52 antagonists/clusterin stimulators, including but not        limited to alemtuzumab;    -   bispecific CD32B/CD79B antibody, including but not limited to        PRV-3279 (MGD-010);    -   CD80 antagonists, including but not limited to abatacept        biobetter;    -   CD80 antagonists/T cell surface glycoprotein CD28 inhibitors,        including but not limited to RhuDex;    -   CD80 antagonists/CD86 antagonists, including but not limited to        XENP-9523 and ASP-2408;    -   CD86 antagonists, including but not limited to abatacept        biosuperior;    -   CD86 antagonists/cytotoxic T-lymphocyte protein-4 modulators,        including but not limited to ES-210;    -   CD95 antagonists, including but not limited to DE-098 and        CS-9507;    -   Cell adhesion molecule inhibitors, including but not limited to        alicaforsen, NPC-17923, TK-280, and PD-144795;    -   Chemokine receptor antagonists, including but not limited to        PF-06835375;    -   Complement C5 factor inhibitors, including but not limited to        eculizumab,    -   Complement C5 factor inhibitors/IL-1 antagonists, including but        not limited to antisense oligonucleotides (rheumatoid arthritis)        and Leiden University Medical Center Complement Factor        stimulators, including but not limited to CM-101;    -   C-reactive protein inhibitors, including but not limited to        ISIS-353512;    -   C-reactive protein inhibitors/cyclooxygenase 2        inhibitors/Nuclear factor kappa B inhibitors/immunoglobulin M        antagonists/IL-2 receptor antagonists/PGE2 antagonists:        IB-RACSF-1 antagonists, including but not limited to masitinib,        FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578,        PD-360324, and JNJ-28312141;    -   CSF-1 antagonists/Fyn tyrosine kinase inhibitors/Kit tyrosine        kinase inhibitors/Lyn tyrosine kinase inhibitors/NK cell        receptor modulators/PDGF receptor antagonists, including but not        limited to masitinib;    -   CXC10 chemokine ligand inhibitors, including but not limited to        946414-98-8 and BMS-936557;    -   CXCR4 chemokine antagonists, including but not limited to        plerixafor;    -   CDK-2/7/9 inhibitors/MCL1 gene inhibitors, including but not        limited to seliciclib;    -   CDK-1/2/5/7/9 inhibitors, including but not limited to BP-14;    -   Chaperonin modulator, including but not limited to IRL-201805;    -   cyclooxygenase 2 inhibitors, including but not limited to        celecoxib, etoricoxib, meloxicam, and lumiracoxib;    -   cyclooxygenase 2/oxidoreductase inhibitors, including but not        limited to etodolac;    -   cyclooxygenase 2 modulators, including but not limited to        DRGT-46;    -   cyclooxygenase inhibitors, including but not limited to        aceclofenac, diclofenac, naproxcinod, naproxen etemesil,        nabumetone, Aleve, pelubiprofen, LY-210073, NS-398, bromfenac,        L-746483, LY-255283, ibuprofen, flurbiprofen, SC-57666, and        bermoprofen;    -   cyclooxygenase inhibitors/H+K+ ATPase inhibitors, including but        not limited to naproxen+esomeprazole strontium;    -   cyclooxygenase inhibitors/PGE1 agonists, including but not        limited to misoprostol+diclofenac;    -   cyclooxygenase inhibitors/oxidoreductase inhibitors, including        but not limited to imidazole salicylate;    -   cytosolic phospholipase A2 inhibitors/phospholipase A2        inhibitors, including but not limited to AVX-002;    -   cytotoxic T-lymphocyte protein-4 stimulators/T cell surface        glycoprotein CD28 inhibitors, including but not limited to        abatacept, BMS-188667, and belatacept;    -   deoxyribonuclease gamma stimulator, including but not limited to        NTR-441;    -   DHFR inhibitors, including but not limited to MPI-2505, Jylamvo,        and ZeNEO-Methotrexate;    -   DHFR inhibitors/folate antagonists/transferrin modulators,        including but not limited to methotrexate;    -   diamine acetyltransferase inhibitors, including but not limited        to diminazene aceturate;    -   dihydroorotate dehydrogenase inhibitors, including but not        limited to ASLAN-003, HWA-486, and ABR-224050;    -   dihydroorotate dehydrogenase/protein tyrosine kinase inhibitors,        including but not limited to leflunomide;    -   DYRK-1 alpha protein kinase inhibitor, including but not limited        to VRN-02;    -   elongation factor 2 inhibitors/interleukin-2 ligands/NAD ADP        ribosyltransferase stimulators, including but not limited to        denileukin diftitox;    -   enolase 1 inhibitor, including but not limited to HuL-001;    -   EP4 prostanoid receptor antagonists, including but not limited        to CR-6086;    -   erythropoietin receptor agonists, including but not limited to        cibinetide;    -   Fas ligands, including but not limited to AP-300;    -   FGF-2 ligand inhibitors, including but not limited to RBM-007;    -   FK506 binding protein-12 modulators/mTOR inhibitors, including        but not limited to temsirolimus;    -   folate antagonists/transferrin modulators/DHFR inhibitors,        including but not limited to MBP-Y003;    -   folate receptor modulators, including but not limited to        technetium (99mTc) etarfolatide;    -   fractalkine ligand inhibitors, including but not limited to        E-6011;    -   Fyn tyrosine kinase inhibitors/GABA A receptor        modulators/cyclooxygenase 2 inhibitors/dihydroorotate        dehydrogenase inhibitors, including but not limited to        laflunimus;    -   glucocorticoid agonists, including but not limited to        prednisone, prednisolone, and fosdagrocorat;    -   glucocorticoid antagonists, including but not limited to        REC-200;    -   glucocorticoid induced leucine zipper stimulators, including but        not limited to ART-G01;    -   GM-CSF ligand inhibitors, including but not limited to        namilumab, gimsilumab (MORAb-022), and TJM-2;    -   GM-CSF receptor antagonists, including but not limited to        mavrilimumab;    -   GM-CSF receptor modulators, including but not limited to        GSK-3196165 and otilimab;    -   growth regulated protein alpha ligand inhibitors/AP1        transcription factor inhibitors/IL-6 antagonists/interleukin-1        beta ligand inhibitors/cathepsin K inhibitors/NFAT gene        inhibitors, including but not limited to T-5224;    -   H+K+ ATPase inhibitors, including but not limited to        naproxen+esomeprazole, ketoprofen+omeprazole, KEO-25001,        HC-1004, and PN-40020;    -   histamine H4 receptor antagonists, including but not limited to        toreforant and GD-48;    -   histone deacetylase inhibitors, including but not limited to        CHR-5154 (GSK-3117391) and NIPEP-CARE;    -   histone deacetylase-6 inhibitors, including but not limited to        CKD-506;    -   HLA class II antigen DQ-2 alpha modulators, including but not        limited to NexVax2;    -   HLA class II antigen inhibitors, including but not limited to        HLA-DR1/DR4 inhibitors (rheumatoid arthritis) and Provid;    -   HLA class II antigen modulators, including but not limited to        recombinant T-cell receptor ligand (rheumatoid arthritis) and        Artielle;    -   Hsp 70 family inhibitors, including but not limited to        gusperimus trihydrochloride;    -   hypoxia inducible factor-1 inhibitors/VEGF receptor antagonists,        including but not limited to 2-methoxyestradiol;    -   IFNB gene stimulators, including but not limited to ART-102;    -   I-kappa B kinase beta inhibitors, including but not limited to        IMD-2560;    -   I-kappa B kinase beta inhibitors/Nuclear factor kappa B        inhibitors, including but not limited to IMD-0560;    -   I-kappa B kinase inhibitors/NFE2L2 gene stimulators/Nuclear        factor kappa B inhibitors/STAT3 gene inhibitors, including but        not limited to bardoxolone methyl;    -   IL-1 antagonists, including but not limited to recombinant human        interleukin-1 receptor antagonist (rheumatoid arthritis),        Shanghai Fudan-Zhangjiang Bio-Pharmaceutical;    -   IL-1 antagonists/interleukin-1 beta ligand inhibitors, including        but not limited to rilonacept;    -   IL-10 agonists, including but not limited to peg-ilodecakin;    -   IL-11 agonists/PDGF receptor agonists, including but not limited        to oprelvekin;    -   IL-12 antagonists/IL-23 antagonists, including but not limited        to ustekinumab and briakinumab;    -   IL-15 antagonists, including but not limited to AMG-714;    -   IL-17 antagonists, including but not limited to ixekizumab and        secukinumab;    -   IL-17 receptor modulators, including but not limited to        CNTO-6785;    -   IL-2 receptor agonists, including but not limited to        interleukin-2 follow-on biologic (IL-2), Anteluke, and        Interking;    -   IL-2/IL-21/IL-15 antagonists, including but not limited to        BNZ-132-2;    -   IL-21 antagonists, including but not limited to NN-8828;    -   IL-4 agonists, including but not limited to SER-130-AMI;    -   IL-6 antagonists, including but not limited to BCD-089,        olokizumab, clazakizumab, sirukumab, SA-237, FB-704A, OP-R003,        peptide IL-6 antagonist, MEDI-5117, AMG-220, FM-101, BLX-1025,        esonarimod, TA-383, and sarilumab;    -   IL-6 antagonists/interleukin-1 beta ligand inhibitors/TNF alpha        ligand inhibitors, including but not limited to K-832;    -   IL-6 antagonists/insulin sensitizers/interleukin-1 beta ligand        inhibitors, including but not limited to BLX-1002;    -   IL-6 receptor antagonists/modulators, including but not limited        to tocilizumab, HS-628, and LusiNEX;    -   IL-6 receptor modulators, including but not limited to BAT-1806        and RO-4877533;    -   immunoglobulin antagonists, including but not limited to        iguratimod;    -   immunoglobulin G1 agonists, including but not limited to BX-2922        and HF-1020;    -   immunoglobulin G1 agonists/interleukin-1 beta ligand inhibitors,        including but not limited to canakinumab;    -   immunoglobulin G1 agonists/TNF alpha ligand inhibitors,        including but not limited to STI-002;    -   immunoglobulin G1 antagonists/TNF alpha ligand inhibitors,        including but not limited to YHB-1411-2;    -   immunoglobulin G1 modulators/GM-CSF ligand        inhibitors/immunoglobulin kappa modulators, including but not        limited to lenzilumab;    -   immunoglobulin G2 antagonists/NF kappa B inhibitor        stimulators/osteoclast differentiation factor        antagonists/osteoclast differentiation factor ligand        inhibitors/TNFSF11 gene inhibitors, including but not limited to        denosumab;    -   immunoglobulin gamma Fc receptor II modulators, including but        not limited to MGD-010;    -   inducible nitric oxide synthase inhibitors/cyclooxygenase 2        inhibitors/MAP kinase modulators/nuclear factor kappa B        inhibitors, including but not limited to SKLB-023;    -   inosine monophosphate dehydrogenase inhibitors, including but        not limited to mizoribine;    -   insulin sensitizers/nuclear factor kappa B        inhibitors/interleukin ligand inhibitors, including but not        limited to HE-3286;    -   integrin alpha-1/beta-1 antagonists, including but not limited        to SAN-300;    -   integrin alpha-4/beta-1 antagonists/cell adhesion molecule        inhibitors, including but not limited to natalizumab;    -   integrin alpha-9 antagonist, including but not limited to        ASP-5094;    -   integrin antagonists, including but not limited to PEG-HM-3 and        CY-9652;    -   interferon beta ligands, including but not limited to        recombinant interferon beta-1a;    -   interferon beta ligands/IL-6 antagonists, including but not        limited to TA-383;    -   interferon gamma ligands, including but not limited to Li Zhu        Yin De Fu and Clongamma;    -   interleukin 17A ligand inhibitors/tumor necrosis factor ligand        inhibitors, including but not limited to ABT-122 and ABBV-257;    -   interleukin 17F ligand inhibitors, including but not limited to        bimekizumab;    -   interleukin 18 ligand inhibitors, including but not limited to        tadekinig alfa;    -   interleukin 23A inhibitors, including but not limited to        guselkumab;    -   interleukin ligands/IL-1 antagonists, including but not limited        to IBPB-007-IL;    -   interleukin receptor 17A antagonists, including but not limited        to brodalumab;    -   interleukin-1 beta ligand inhibitors, including but not limited        to gevokizumab, LY-2189102, CDP-484, and AR-100;    -   interleukin-1 beta ligand inhibitors/TNF alpha ligand        inhibitors, including but not limited to PMI-001;    -   interleukin-1 beta ligands/TNF alpha ligand modulators,        including but not limited to PUR-0110;    -   interleukin-2 ligands, including but not limited to recombinant        interleukin-2 and CUG-252;    -   IL-2 modulators, including but not limited to AMG-592;    -   interleukin-4 ligands/tenascin modulator, including but not        limited to Tetravil;    -   interleukin-6 ligand inhibitors, including but not limited to        gerilimzumab and PF-4236921;    -   IRAK-4 protein kinase inhibitor, including but not limited to        BAY-1830839, BAY-1834845, PF-06650833, and KT-474;    -   Itk tyrosine kinase inhibitors, including but not limited to        JTE-051;    -   Itk tyrosine kinase inhibitors/Jak3 tyrosine kinase inhibitors,        including but not limited to ARN-4079;    -   JAK tyrosine kinase inhibitors, including but not limited to        deuterated tofacitinib analog, SD-900, and WXSH-0150;    -   JAK tyrosine kinase inhibitors/Syk tyrosine kinase inhibitors,        including but not limited to cerdulatinib and CVXL-0074;    -   Jak1 tyrosine kinase inhibitors, including but not limited to        ABT-494 (upadacitinib), ruxolitinib, filgotinib, itacitinib,        NIP-585, YJC-50018, GLPG-0555, MRK-12, and SHR-0302;    -   Jak1/3 tyrosine kinase inhibitors, including but not limited to        tofacitinib, tofacitinib citrate, peficitinib, CKD-374, and        CS-944X;    -   JAK 1/3 inhibitor/ROCK1/2 inhibitor: CPL-409116    -   Jak1/2 tyrosine kinase inhibitors, including but not limited to        baricitinib, ruxolitinib, LW-104, and TLL-018;    -   Jak2 tyrosine kinase inhibitors/CSF-1 antagonists, including but        not limited to CT-1578;    -   JAK3 gene inhibitors, including but not limited to PF-06651600;    -   Jak3 tyrosine kinase inhibitors, including but not limited to        decernotinib, DNX-04042, MTF-003, and PS-020613;    -   Jun N terminal kinase inhibitors, including but not limited to        IQ-1S;    -   KCNA voltage-gated potassium channel-3 modulators, including but        not limited to MRAD-P1;    -   Kelch like ECH associated protein 1 modulators/Nuclear erythroid        2-related factor 2 stimulators, including but not limited to        dimethyl fumarate;    -   LanC like protein 2 modulators, including but not limited to        BT-11 and BT-104;    -   LDL receptor related protein-1 stimulator, including but not        limited to SP-16;    -   leukotriene BLT receptor antagonists/complement C5 factor        inhibitors, including but not limited to nomacopan;    -   LITAF gene inhibitors/JAK3 gene inhibitors/MAP3K2 gene        inhibitors/TNF antagonists, including but not limited to GBL-5b;    -   Lymphocyte function antigen-3 receptor antagonists, including        but not limited to alefacept;    -   Macrophage mannose receptor 1 modulators, including but not        limited to technetium Tc 99m tilmanocept;    -   MAdCAM inhibitors/immunoglobulin G2 modulators, including but        not limited to PF-547659;    -   MAPKAPK5 inhibitors/matrix metalloprotease inhibitors, including        but not limited to GLPG-0259;    -   MEK protein kinase inhibitors, including but not limited to        AD-GL0001;    -   membrane copper amine oxidase inhibitors, including but not        limited to BTT-1023, PRX-167700, and vepalimomab;    -   metalloprotease-9 inhibitors, including but not limited to        GS-5745;    -   microbiome modulator, including but not limited to EDP-1815;    -   midkine ligand inhibitors, including but not limited to CAB-102;    -   mitochondrial 10 kDa heat shock protein stimulators, including        but not limited to INV-103;    -   mTOR inhibitors, including but not limited to everolimus;    -   NAMPT gene inhibitors, including but not limited to ART-D01;    -   Nicotinic acetylcholine receptor antagonists, including but not        limited to RPI-78 and RPI-MN;    -   NKG2 A B activating NK receptor antagonists, including but not        limited to monalizumab;    -   NKG2 D activating NK receptor antagonists, including but not        limited to NNC-0142-002;    -   nuclear factor kappa B inhibitors, including but not limited to        dehydroxymethylepoxyquinomicin, MP-42, VGX-1027, SP-650003,        MG-132, SIM-916, VGX-350, VGX-300, GIT-027, MLN-1145, and        NVP-IKK-005;    -   nuclear factor kappa B modulators/nuclear factor kappa B p105        inhibitors/transcription factor RelB inhibitors/transcription        factor p65 inhibitors, including but not limited to REM-1086;    -   osteoclast differentiation factor antagonists, including but not        limited to cyclic peptidomimetics (rheumatoid        arthritis/osteoporosis), University of Michigan;    -   p38 aMAP kinase alpha inhibitors, including but not limited to        VX-745, BMS-582949, and BMS-751324;    -   p38 MAP kinase inhibitors, including but not limited to BCT-197,        losmapimod, and ARRY-797;    -   PDE 4 inhibitors, including but not limited to apremilast;    -   PDE 5 inhibitors, including but not limited to PDE5 inhibitors        (rheumatoid arthritis), University of Rochester;    -   PDGF-B ligand inhibitors/VEGF receptor antagonists, including        but not limited to SL-1026;    -   phosphoinositide-3 kinase delta inhibitors, including but not        limited to CT-732, INK-007, and GNE-293;    -   phosphoinositide-3 kinase delta/gamma inhibitors, including but        not limited to duvelisib and RP-6503;    -   phospholipase A2 inhibitors, including but not limited to        AK-106, varespladib methyl, Ro-31-4493, BM-162353, Ro-23-9358,        and YM-26734;    -   platelet activating factor receptor antagonists, including but        not limited to piperidone hydrochloridum;    -   PPAR gamma agonists, including but not limited to rosiglitazone        XR;    -   PPAR gamma agonists/insulin sensitizers, including but not        limited to rosiglitazone;    -   programmed cell death protein 1 modulators, including but not        limited to INSIX RA;    -   prostaglandin D synthase stimulators, including but not limited        to HF-0220;    -   protein tyrosine kinase inhibitors, including but not limited to        tairuimide;    -   PurH purine biosynthesis protein inhibitors/inosine        monophosphate dehydrogenase inhibitors, including but not        limited to mycophenolate mofetil;    -   Rev protein modulators, including but not limited to ABX-464;    -   RIP-1 kinase inhibitors, including but not limited to        GSK-2982772 and VRN-04;    -   IL-17 antagonist/rho associated protein kinase 2 inhibitor,        including but not limited to KD-025;    -   signal transducer CD24 modulators, including but not limited to        CD24-IgFc;    -   sodium glucose transporter-2 inhibitors/PPAR gamma        agonists/insulin sensitizers, including but not limited to        THR-0921;    -   STAT3 gene inhibitors, including but not limited to        vidofludimus;    -   STAT-3 inhibitors, including but not limited to HL-237;    -   Superoxide dismutase stimulators, including but not limited to        imisopasem manganese;    -   SYK family tyrosine kinase inhibitors/Zap70 tyrosine kinase        inhibitors, including but not limited to MK-8457;    -   Syk tyrosine kinase inhibitors, including but not limited to        fostamatinib, entospletinib, KDDF-201110-06, HMPL-523, AB-8779,        GS-9876, PRT-2607, CG-103065, and SKI-0-703;    -   T cell receptor antagonists, including but not limited to TCR        inhibiting SCHOOL peptides (systemic/topical, rheumatoid        arthritis/dermatitis/scleroderma), SignaBlok and CII modified        peptide (rheumatoid arthritis);    -   T cell receptor modulators/HLA class II antigen modulators,        including but not limited to ARG-301;    -   T cell surface glycoprotein CD28 stimulators, including but not        limited to TAB-08 and theralizumab;    -   TAK1 binding protein modulators, including but not limited to        epigallocatechin 3-gallate;    -   Talin modulators, including but not limited to short-form talin        regulators (rheumatoid arthritis), KayteeBio;    -   T-cell differentiation antigen CD6 inhibitors, including but not        limited to itolizumab;    -   T-cell surface glycoprotein CD8 inhibitors/TGF beta agonists/CD4        antagonists, including but not limited to tregalizumab;    -   thymulin agonists, including but not limited to Syn-1002;    -   TLR-2/TLR-4 antagonists, including but not limited to VB-201;    -   TLR-4 antagonists, including but not limited to NI-0101;    -   TLR-2/4/9 antagonists, including but not limited to P-13;    -   TNF agonists/TNF antagonists/type II TNF receptor modulators,        including but not limited to Lifmior;    -   TNF alpha ligand inhibitors, including but not limited to        Adfrar, FKB-327, Exemptia, Cinnora, Mabura, adalimumab,        infliximab, Flixabi, PF-06438179, hadlima, recombinant humanized        anti-TNF-alpha monoclonal antibody, CMAB-008, CT-P13, GB-242,        golimumab (CNTO-148), ozoralizumab, AT-132, ISIS-104838,        ISU-202, CT-P17, MB-612, Debio-0512, anti-TNF alpha human        monoclonal antibody, UB-721, KN-002, DA-3113, BX-2922,        R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420, GS-071,        ABP-710, BOW-015, HLX-03, BI-695501, MYL-1401A, ABP-501,        BAX-2923, SCH-215596, ABT-D2E7, BAT-1406, XPro-1595, Atsttrin,        SSS-07, golimumab biosimilar, TA-101, BLX-1002, ABX-0401,        TAQ-588, TeHL-1, placulumab, CYT-007-TNFQb, SSR-150106, PassTNF,        Verigen, DOM-0200, DOM-0215, AME-527, anti-TNF-alpha mAb,        GENZ-38167, BLX-1028, CYT-020-TNFQb, CC-1080, CC-1069, LBAL,        GP-2017, Idacio, IBI-303, HS-016, TNF-2, and IA-14069;    -   TNF alpha ligand inhibitors/TNF antagonists/type II TNF receptor        modulators, including but not limited to BAX-2200;    -   TNF alpha ligand inhibitors/Type II TNF receptor modulators,        including but not limited to Eucept, TNF alpha ligand        modulators: MM-A01-01, CDP-571, camobucol, and JNJ-63823539;    -   TNF antagonists, including but not limited to DNX-114, TNF        antagonist+IL-12 antagonist (rheumatoid arthritis), University        of Oxford, BN-006, pegsunercept, ACE-772, onercept, DE-096,        PN-0615, lenercept, ITF-1779, MDL-201112, HD-203, Qiangke, and        TNF a Fc;    -   TNF antagonists/type II TNF receptor modulators, including but        not limited to Altebrel, Intacept, QL-0902, etanercept, Erelzi,        opinercept, YISAIPU, Anbainuo, Benepali, YLB-113, SCB-808,        DA-3853, and SCB-131;    -   TNF antagonists/TNF alpha ligand inhibitors, including but not        limited to certolizumab pegol;    -   TNF receptor modulators, including but not limited to        recombinant TNF receptor 2-Fc fusion protein mutant, T-0001;    -   TNF receptor modulators/TNF alpha ligand inhibitors, including        but not limited to tgAAV-TNFR:Fc;    -   tumor necrosis factor 13C receptor antagonists, including but        not limited to VAY-736;    -   tumor necrosis factor 15 ligand inhibitors, including but not        limited to anti-TL1A antibodies (rheumatoid        arthritis/inflammatory bowel disease), NIAMS;    -   tumor necrosis factor ligand inhibitors, including but not        limited to etanercept biosimilar;    -   type I IL-1 receptor antagonists, including but not limited to        anakinra, IL-1 R^(a), anakinra follow-on biologic, and AXXO;    -   type I TNF receptor antagonists, including but not limited to        NM-940 and EN-2001;    -   type II TNF receptor modulators, including but not limited to        LBEC-0101, DMB-3853, DWP-422, and BT-D001;    -   unspecified GPCR agonists, including but not limited to NCP-70X;    -   VEGF receptor antagonists, including but not limited to        NSC-650853;    -   VEGF-2 receptor modulators, including but not limited to VEGFR2        neutralizing antibody (rheumatoid arthritis), University of        Rochester;    -   VEGF-B ligand inhibitors, including but not limited to CSL-346;    -   X-linked inhibitor of apoptosis protein inhibitors, including        but not limited to IAP inhibitors (oral), Pharmascience; and    -   Zap70 tyrosine kinase inhibitors, including but not limited to        CT-5332.

Inflammatory Bowel Disease Combination Therapy

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one or more additionaltherapeutic agents that treat or ameliorate inflammatory bowel disease(IBD).

The term “inflammatory bowel disease” or “IBD” as used herein is acollective term describing inflammatory disorders of thegastrointestinal tract, the most common forms of which are ulcerativecolitis and Crohn's disease. Other forms of IBD that can be treated withthe compounds provided herein, or pharmaceutically acceptable saltsthereof, or pharmaceutical compositions provided herein include, but arenot limited to, diversion colitis, ischemic colitis, infectious colitis,chemical colitis, microscopic colitis (including collagenous colitis andlymphocytic colitis), atypical colitis, pseudomembranous colitis,fulminant colitis, autistic enterocolitis, indeterminate colitis,Behget's disease, gastroduodenal CD, jejunoileitis, ileitis,ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome,mucositis, radiation induced enteritis, short bowel syndrome, celiacdisease, stomach ulcers, diverticulitis, pouchitis, proctitis, andchronic diarrhea.

Treating or preventing IBD also includes ameliorating or reducing one ormore symptoms of IBD. As used herein, the term “symptoms of IBD” refersto detected symptoms such as abdominal pain, diarrhea, rectal bleeding,weight loss, fever, loss of appetite, and other more seriouscomplications, such as dehydration, anemia and malnutrition. A number ofsuch symptoms are subject to quantitative analysis (e.g. weight loss,fever, anemia, etc.). Some symptoms are readily determined from a bloodtest (e.g. anemia) or a test that detects the presence of blood (e.g.rectal bleeding). The term “wherein said symptoms are reduced” refers toa qualitative or quantitative reduction in detectable symptoms,including but not limited to a detectable impact on the rate of recoveryfrom disease (e.g. rate of weight gain). The diagnosis is typicallydetermined by way of an endoscopic observation of the mucosa, andpathologic examination of endoscopic biopsy specimens.

The course of IBD varies and is often associated with intermittentperiods of disease remission and disease exacerbation. Various methodshave been described for characterizing disease activity and severity ofIBD as well as response to treatment in subjects having IBD. Treatmentaccording to the present methods and uses is generally applicable to asubject having IBD of any level or degree of disease activity.

The methods and uses provided herein can also be applied at any point inthe course of the disease. In some embodiments, the methods and uses areapplied to a subject having IBD during a time period of remission (i.e.,inactive disease). In some embodiments, the present methods and usesprovided herein provide benefit by extending the time period ofremission (e.g., extending the period of inactive disease) or bypreventing, reducing, or delaying the onset of active disease. In someembodiments, the methods and uses provided herein may be applied to asubject having IBD during a period of active disease. In someembodiments, the methods and uses provided herein provide benefit byreducing the duration of the period of active disease, reducing orameliorating one or more symptoms of IBD, or treating IBD.

Measures for determining efficacy of treatment of IBD in clinicalpractice have been described and include, for example, the following:symptom control; fistula closure; extent of corticosteroid therapyrequired; and improvement in quality of life. Heath-related quality oflife (HRQL) can be assessed using the Inflammatory Bowel DiseaseQuestionnaire (IBDQ), which is extensively used in clinical practice toassess quality of life in a subject with IBD. (See Guyatt et al. (1989)Gastroenterology 96:804-810.)

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one or more additionaltherapeutic agents that treat or ameliorate IBD. Non-limiting examplesof therapeutic agents that treat or ameliorate IBC include allogeneicbone marrow-derived MSC therapy, AMP activated protein kinasestimulator, aryl hydrocarbon receptor agonist and T cell receptormodulator, ASK1 inhibitors, beta adrenoceptor antagonists, BTKinhibitors, beta-catenin stimulator, beta-glucuronidase inhibitors,bradykinin receptor modulators, calcineurin inhibitors, calcium channelinhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15gene inhibitors, collagen modulators, CXCR3 chemokine antagonist, CSF-1antagonists, cyclooxygenase inhibitors, cytochrome P450 3A4 inhibitors,DYRK-1 alpha protein kinase inhibitor, endothelial dysfunction andvascular leakage blocker, enolase 1 inhibitor, eotaxin ligandinhibitors, EP4 prostanoid receptor agonists, erythropoietin receptoragonists, exportin 1 inhibitor, fractalkine ligand inhibitors, freefatty acid receptor 2 antagonists, GATA 3 transcription factorinhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists,guanylate cyclase receptor agonists, histone deacetylase inhibitors, HLAclass II antigen modulators, IL-12 antagonists, IL-13 antagonists,Interleukin-2 ligand, IL-23 antagonists, IL-6 antagonists, IL-6 receptormodulators, interleukin-7 receptor modulators, IL-7 antagonists, IL-8antagonists, integrin alpha-4/beta-1 antagonists, integrinalpha-4/beta-7 antagonists, integrin alpha-E antagonists, integrinantagonists, integrin beta-7 antagonists, interleukin ligand inhibitors,Interleukin-10 ligand, interleukin receptor 17A antagonists, Interleukin23A inhibitor, interleukin-1 beta ligands, interleukin-1 beta ligandmodulators, IRAK4 inhibitors, JAK tyrosine kinase inhibitors, Jak1tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, LanC likeprotein 2 modulators, lipoxygenase modulators, acrophage mannosereceptor 1 modulator, MAdCAM inhibitors, matrix metalloproteaseinhibitors, melanocortin agonists, metalloprotease-9 inhibitors, NADPHoxidase inhibitor, natriuretic peptide receptor C agonists, NC-301,next-generation intestinal microbiota therapy, neuregulin-4 ligands,NKG2 D activating NK receptor antagonists, Non receptor tyrosine kinaseTYK2 antagonist, opioid receptor antagonists, opioid receptor deltaantagonists, oxidoreductase inhibitors, P2X7 purinoceptor agonists, PDE4 inhibitors, phagocytosis stimulating peptide modulators, potassiumchannel inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gammaagonists, protein fimH inhibitors, P-selectin glycoprotein ligand-1inhibitors, RNA polymerase inhibitors, sphingosine 1 phosphatephosphatase 1 stimulators, sphingosine 1 phosphate phosphatasemodulators, sphingosine-1-phosphate receptor-1 agonists,sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphatereceptor-1 modulators, sphingosine-1-phosphate receptor-5 modulators,STAT3 gene inhibitors, stem cell antigen-1 inhibitors, superoxidedismutase modulators, superoxide dismutase stimulators, SYK inhibitors,TGF beta 1 ligand inhibitors, thymulin agonists, TLR antagonists, TNFalpha ligand inhibitors, TNF antagonists, tumor necrosis factor 14ligand modulators, type II TNF receptor modulators, Tpl 2 inhibitors, Xbox binding protein 1 stimulator, and Zonulin inhibitors.

In some embodiments, the compounds provided herein, or pharmaceuticallyacceptable salts thereof, may be combined with one or more additionaltherapeutic agents selected from ABX-464, adalimumab; ALLO-ASC-CD,AMG-966, AMT-101, anakinra, apremilast; Alequel; ALV-304, AMG-139;amiselimod, anti-CXCR3 mAb, ASD-003, ASP-3291, AX-1505, balsalazide;beclomethasone dipropionate; BI-655130, BMC-321, BMC-322, BMS-986184;BT-051, budesonide; CBX-11, CEQ-508; certolizumab; cibinetide,Clostridium butyricum; ChAdOx2-HAV, CU-06, CUG-252 dexamethasone sodiumphosphate, DNVX-078, EB-7020, EM-101, etanercept; ENERGI-F704, ETX-201,golimumab; GS-4997, GS-5718, GS-9876, GS-4875, GS-4059, infliximab;IMS-001, mesalazine, HLD-400, IBI-112, IMM-H013, KB-295, LFS-829,LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500, JNJ-66525433, JNJ-4447,mesalamine, MET-642, MVA-HAV, naltrexone; natalizumab; neihulizumab,olsalazine; NOS-1244, NTG-A-009, PH-46-A, propionyl-L-carnitine;PTG-100; remestemcel-L; tacrolimus; teduglutide; tofacitinib; ASP-1002;ustekinumab; vedolizumab; AVX-470; INN-108; SGM-1019; PF-06480605;PF-06651600; PR-600; RBX-8225, R-2187, RG-6287, SER-287; TOP-1288;VBY-129; 99mTc-annexin V-128; bertilimumab; DLX-105; dolcanatide;quetmolimab (E-6011); FFP-104; filgotinib; foralumab; GED-0507-34-Levo;givinostat; GLPG-0974; iberogast; ICP-330, JNJ-40346527; K(D)PT;KAG-308; KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase;olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RG-7835;RBX-2660, RO7049665, JKB-122; SYGN-313, SB-012; STNM-01; SZN-1326,TJC-0434, Debio-0512; TRK-170; ABT-494; Ampion; BI-655066; carotegastmethyl; cobitolimod; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02,ozanimod; peficitinib; QX-004-N, RHB-104; SEFA-1024, tildrakizumab;TOP-1890, tralokinumab; brodalumab; laquinimod; and plecanatide; or apharmaceutically acceptable salt of any of the foregoing; or anycombination thereof.

VII. Compound Preparation

Some embodiments of the present disclosure are directed to processes andintermediates useful for preparing the compounds provided herein orpharmaceutically acceptable salts thereof.

Compounds described herein can be purified by any of the means known inthe art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography.

During any of the processes for preparation of the compounds providedherein, it may be necessary and/or desirable to protect sensitive orreactive groups on any of the molecules concerned. This may be achievedby means of conventional protecting groups as described in standardworks, such as T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” 4^(th) ed., Wiley, New York 2006. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used.

The methods of the present disclosure generally provide a specificenantiomer or diastereomer as the desired product, although thestereochemistry of the enantiomer or diastereomer was not determined inall cases. When the stereochemistry of the specific stereocenter in theenantiomer or diastereomer is not determined, the compound is drawnwithout showing any stereochemistry at that specific stereocenter eventhough the compound can be substantially enantiomerically ordiastereomerically pure.

Representative syntheses of compounds of the present disclosure aredescribed in the schemes below, and the particular examples that follow.

Certain abbreviations and acronyms are used in describing theexperimental details. Although a person of ordinary skill in the artwill readily recognize and understand most of the abbreviations andacronyms, the below list provides many of the meanings of theabbreviations and acronyms.

List of Abbreviations and Acronyms Abbreviation Meaning Ac acetate AcOHacetic acid ACN acetonitrile AmPhosdi-tert-butyl(4-dimethylaminophenyl)phosphine Bn benzyl Bpin(pinacolato)boron B₂Pin₂ bis(pinacolato)diboron Boc tert-butoxycarbonylBoc₂O di-tert-butyl dicabonate Bu Butyl Bz benzoyl BzCl benzoyl chloridecataCXium ® A Pd G3Mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) CDI 1,1′-carbonyldiimidazole DBAD di-tert-butylazodicarboxylate DBU 1,8-Diazabicyclo[5. 4. 0]undec-7-ene DCE1,2-dichloroethane DCM dichloromethane DEA diethylamine DeoxofluorBis(2-methoxyethyl)aminosulfur trifluoride DIPEAN,N-diisopropylethylamine DMA dimethylacetamide 4-DMAP4-dimethylaminopyridine DME dimethoxyethane DMF dimethylformamideDMF-DMA N,N-dimethylformamide dimethyl acetal DMSO dimethylsulfoxidedppf 1,1′-Ferrocenediyl-bis(diphenylphosphine) dtbbpy4,4′-Di-tert-butyl-2,2′-dipyridyl EDCN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EDCIN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ES/MSelectron spray mass spectrometry Et ethyl HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HNMR hydrogen nuclear magnetic resonance IPAisopropanol JohnPhos (2-Biphenyl)di-tert-butylphosphine KOtBu potassiumtert-butoxide LC liquid chromatography LCMS liquid chromatography/massspectrometry MCPBA meta-chloroperbenzoic acid Me methyl Msmethanesulfonyl m/z mass to charge ratio MS or ms mass spectrum NBSN-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMPN-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd(AmPhos)₂Cl₂Bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II)Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Ph phenyl Ph₃P triphenylphosphine Pg Protecting group pin pinacol Pivpivaloyl PMB para-methoxybenzyl Pyr pyridine RBF round bottom flaskRP-HPLC reverse phase high performance liquid chromatography RT roomtemperature SEM [2-(trimethylsilyl)ethoxy]methyl SFC supercritical fluidchromatography STAB Sodium triacetoxyborohydride TBAI Tetrabutylammoniumiodide TLC thin layer chromatography tBuXPhos Pd G3[(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2- (2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate XantPhos4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos Pd G2Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) XPhos Pd G3(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate TBAFTetrabutylammonium fluoride TCFHChloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate TEAtriethylamine TFA trifluoroacetic acid THF tetrahydrofuran Tftrifluoromethanesulfonyl Ts 4-toluenesulfonyl δ parts per millionreferenced to residual solvent peak

General Synthetic Schemes

General Reaction Schemes 1-14 are provided as further embodiments of thepresent disclosure and illustrate general methods which were used toprepare certain compounds of the present disclosure and which can beused to prepare additional compounds of the present disclosure. Each ofthe variables (e.g. R¹, R², R³, R⁴) of the compounds disclosed inGeneral Reaction Schemes 1-13 are as defined herein.

The compounds of the present disclosure may be prepared using themethods disclosed herein and routine modifications thereof, which willbe apparent to a skilled artisan given the disclosure herein and methodswell known in the art. Conventional and well-known synthetic methods maybe used in addition to the teachings herein. The synthesis of typicalcompounds described herein may be accomplished as described in thefollowing examples. If available, reagents may be purchasedcommercially, e.g., from Sigma Aldrich or other chemical suppliers. Ingeneral, compounds described herein are typically stable and isolatableat room temperature and pressure.

Typical embodiments of compounds disclosed herein may be synthesizedusing the general reaction schemes described below. It will be apparentto a skilled artisan given the description herein that the generalschemes may be altered by substitution of the starting materials withother materials having similar structures to result in products that arecorrespondingly different. Descriptions of syntheses follow to providenumerous examples of how the starting materials may vary to providecorresponding products. Given a desired product for which thesubstituent groups are defined, the necessary starting materialsgenerally may be determined by inspection. Starting materials aretypically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodimentsdisclosed in the present disclosure, inspection of the structure of thecompound to be synthesized will provide the identity of each substituentgroup. The identity of the final product will generally render apparentthe identity of the necessary starting materials by a simple process ofinspection, given the examples herein.

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, and the like). Unless specified to the contrary, the solventsused in the reactions of the present disclosure are inert organicsolvents, and the reactions are carried out under an inert gas,preferably nitrogen or argon.

Intermediate 1.1 (where M is —B, —Sn, —Zn, —Si, or —Mg) may be reactedwith Intermediate 2 in the presence of a suitable palladium catalyst todeliver intermediate 1.3. Intermediate 1.4 may be reacted in thepresence of a metalating reagent (e.g. iPrMgBr, n-BuLi) and di-tertbutylazodicarboxylate to afford Intermediate 1.6. Intermediate 1.3 may bereacted with intermediate 1.6 at elevated temperatures in the presenceof acid (e.g. PTSA) to afford Intermediate 1.7.

Intermediate 1.7 can be reacted in the presence of a suitable base (e.g.LiOH, Me₃SnOH) and heat to produce Intermediate 2.1. Intermediate 2.1may then be reacted in the presence of a suitable base (e.g. DBU) andheat for produce intermediate 2.2. Alternatively, Intermediate 2.2 maybe furnished by reacting Intermediate 1.7 in the presence of a suitablebase (e.g. LiOH) and extended heating. Intermediate 2.2 may be reactedwith Boc-anhydride in the presence of a suitable base (e.g. DMAP) toafford Intermediate 2.3. Intermediate 2.3 may be reacted in the presenceof suitable halogenating reagent (e.g., NBS, NIS, NCS) to produceintermediate 2.4, where X=I, Br, or Cl.

Compounds of formula (I.a) can be assembled by the combination ofintermediate 2.1 with a suitable primary or secondary amine 3.1, in thepresence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC)and a suitable base (e.g., N,N-diisopropylethylamine, triethylamine). Ifthe compound of the formula (I.a) contains a tert-butylcarbamatefunctional group, this can be subsequently removed by treatment withacid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal acompound of formula (I.a) that contains a primary or secondary amine. Ifthe compound of the formula (I.a) contains a benzyl-amine functionalgroup, this can be subsequently removed (e.g., using a metal catalystand H₂ gas), to reveal a compound of formula (I.a) that contains aprimary or secondary amine.

Compounds of formula (I.b) can be assembled by the combination ofintermediate 2.1 with a suitable cyclic secondary amine 4.1, in thepresence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC)and a suitable base (e.g., N,N-diisopropylethylamine, triethylamine). Ifthe compound of the formula (I.b) contains a tert-butylcarbamatefunctional group, this can be subsequently removed by treatment withacid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal acompound of formula (I.b) that contains a primary or secondary amine. Ifthe compound of the formula (I.b) contains a benzyl-amine functionalgroup, this can be subsequently removed (e.g., using a metal catalystand H₂ gas), to reveal a compound of formula (I.b) that contains aprimary or secondary amine.

Compounds of the formula (I.c) that contain an (1,3,4)-oxadiazole moietymay be assembled by reacting intermediate 2.1 with an intermediate 5.1first in the presence of a suitable peptide coupling reagent (e.g.,HATU, TCFH, EDC, CDI) and a suitable base (e.g.,N,N-diisopropylethylamine, triethylamine), and then subsequently in thepresence of an oxidant (e.g., Burgess reagent). Alternatively, compoundsof the formula (I.d) that contain a (1,3,4)-thiadiazole moiety may beassembled by reacting intermediate 2.1 with an intermediate 5.1 first inthe presence of a suitable peptide coupling reagent (e.g., HATU, TCFH,EDC, CDI) and a suitable base (e.g., N,N-diisopropylethylamine,triethylamine), and then subsequently in the presence of an sulfurreagent (e.g., Lawesson's reagent, P₂S₅). If the compound of the formula(I.c) or (I.d) contains a tert-butylcarbamate functional group, this canbe subsequently removed by treatment with acid (e.g., trifluoroaceticacid or hydrochloric acid) to reveal a compound of formula (I.c) or(I.d) that contains a primary or secondary amine. If the compound of theformula (I.c) or (I.d) contains a benzyl-amine functional group, thiscan be subsequently removed (e.g., using a metal catalyst and H₂ gas),to reveal a compound of formula (I.c) or (I.d) that contains a primaryor secondary amine.

Compounds of the formula (I.e) that contain an (1,2,4)-oxadiazole moietymay be assembled by reacting intermediate 2.1 with an intermediate 6.1first in the presence of a coupling reagent (e.g., CDI) and heat. If thecompound of the formula (I.e) contains a tert-butylcarbamate functionalgroup, this can be subsequently removed by treatment with acid (e.g.,trifluoroacetic acid or hydrochloric acid) to reveal a compound offormula (I.e) that contains a primary or secondary amine. If thecompound of the formula (I.e) contains a benzyl-amine functional group,this can be subsequently removed (e.g., using a metal catalyst and H₂gas), to reveal a compound of formula (I.e) that contains a primary orsecondary amine.

Compounds of the formula (I.f) that contain an oxazoline moiety may beassembled by reacting intermediate 2.1 with an intermediate 7.1 first inthe presence of a suitable peptide coupling reagent (e.g., HATU, TCFH,EDC, CDI) and a suitable base (e.g., N,N-diisopropylethylamine,triethylamine), and then subsequently in the presence of an oxidant(e.g., Burgess reagent). Alternatively, compounds of the formula (I.g)that contain an oxazoline moiety may be assembled by reactingintermediate 2.1 with an intermediate 7.2 first in the presence of asuitable peptide coupling reagent (e.g., HATU, TCFH, EDC, CDI) and asuitable base (e.g., N,N-diisopropylethylamine, triethylamine), and thensubsequently in the presence of an oxidant (e.g., Burgess reagent). Ifthe compound of the formula (I.f) or (I.g) contains atert-butylcarbamate functional group, this can be subsequently removedby treatment with acid (e.g., trifluoroacetic acid or hydrochloric acid)to reveal a compound of formula (I.f) or (I.g) that contains a primaryor secondary amine. If the compound of the formula (I.f) or (I.g)contains a benzyl-amine functional group, this can be subsequentlyremoved (e.g., using a metal catalyst and H₂ gas), to reveal a compoundof formula (I.f) or (I.g) that contains a primary or secondary amine.

Compounds of formula (I.h) can be assembled by the combination ofintermediate 2.4 with a suitable metallated coupling partner M-Z (whereZ is aryl, heteroaryl, alkenyl, and M is —B, —Sn, —Zn, —Si, or —Mg)using a suitable palladium catalyst and a base (e.g., cesium carbonate,potassium phosphate tribasic, sodium carbonate) to deliver compounds offormula (I.h). If the compound of formula (I.h) contains an alkene, thiscan be subsequently removed (e.g., using a metal catalyst and H₂ gas).If the compound of the formula (I.h) contains a tert-butylcarbamatefunctional group, this can be subsequently removed by treatment withacid (e.g., trifluoroacetic acid or hydrochloric acid) to reveal acompound of formula (I.h) that contains a primary or secondary amine. Ifthe compound of the formula (I.h) contains a benzyl-amine functionalgroup, this can be subsequently removed (e.g., using a metal catalystand H₂ gas), to reveal a compound of formula (I.h) that contains aprimary or secondary amine.

Compounds of formula (I.j) can be assembled by the combination of acompound of formula (L.i) (produced via one of the methods elaboratedabove, such as Scheme 3) with a suitable carboxylic acid 9.1, in thepresence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC)and a suitable base (e.g., N,N-diisopropylethylamine, triethylamine).Alternatively, compounds of formula (I.k) can be assembled by thecombination of compounds of formula (I.i) with a suitable aldehyde 9.2,in the presence of a suitable reducing reagent (e.g., NaBH₄, Na(OAc)₃BH,Na(CN)₃BH). Alternatively, compounds of formula (I.l) can be assembledby the combination of compounds of formula (I.i) with an intermediate9.3, where X is a leaving group (e.g. —Cl, —Br, —I, OTs, —OMs), in thepresence of a base (e.g., N,N-diisopropylethylamine, triethylamine,K₂CO₃, CsCO₃). If the compound of the formula (I.j.), (I.k), or (I.l)contains a tert-butylcarbamate functional group, this can besubsequently removed by treatment with acid (e.g., trifluoroacetic acidor hydrochloric acid) to reveal a compound of formula (I.j.), (I.k), or(I.l) that contains a primary or secondary amine. If the compound of theformula (I.j.), (I.k), or (I.l) contains a benzyl-amine functionalgroup, this can be subsequently removed (e.g., using a metal catalystand H₂ gas), to reveal a compound of formula (I.j.), (I.k), or (I.l)that contains a primary or secondary amine.

Intermediate 2.4 can be coupled with intermediate 10.1 (where -M is —B,—Sn, or —Zn, and Pg is Boc or Bn) in the presence of a palladiumcatalyst and a base (e.g., cesium carbonate, potassium phosphatetribasic, sodium carbonate) to produce intermediate 10.2. Intermediate10.2 may be reacted in the presence of a metal catalyst (e.g.,palladium) and H₂ gas to produce Intermediate 10.3. Alternatively,Intermediate 2.4 can be coupled with intermediate 10.4 (where -M is —Bor —Zn, and Pg is Boc or Bn) in the presence of a palladium catalyst toproduce intermediate 10.3. Alternatively, Intermediate 2.4 can becoupled with intermediate 10.5 (where —X is —Cl, —Br, —I, OMs, —OTs,—OTf, and Pg is Boc or Bn) in the presence of a palladium or nickelcatalyst to produce intermediate 10.3. Intermediate 10.3 may be reactedin the presence of aqueous base (e.g. potassium carbonate) to affordIntermediate 10.6. If Pg=Boc, Intermediate 10.6 may be reacted in thepresence of acid (e.g., TFA, HCl) to produce a compound of formula(I.m). Alternatively, if Pg=Bn, Intermediate 10.6 may be reacted in thepresence of a metal catalyst (e.g., palladium) and H₂ gas to produce acompound of formula (I.m).

Compounds of formula (I.n) can be assembled by the combination of acompound of formula (I.m) (produced via one of the methods elaboratedabove, such as Scheme 10) with a suitable carboxylic acid 11.1, in thepresence of a suitable peptide coupling reagent (e.g., HATU, TCFH, EDC)and a suitable base (e.g., N,N-diisopropylethylamine, triethylamine).Alternatively, compounds of formula (I.o) can be assembled by thecombination of compounds of formula (I.m) with a suitable aldehyde orketone 11.2, in the presence of a suitable reducing reagent (e.g.,NaBH₄, Na(OAc)₃BH, Na(CN)₃BH). Alternatively, compounds of formula (I.p)can be assembled by the combination of compounds of formula (I.m) withan intermediate 10.3, where X is a leaving group (e.g. —Cl, 0Br, —I,OTs, —OMs), in the presence of a base (e.g., N,N-diisopropylethylamine,triethylamine, K₂CO₃, CsCO₃). If the compound of the formula (I.n),(I.o), or (I.p) contains a tert-butylcarbamate functional group, thiscan be subsequently removed by treatment with acid (e.g.,trifluoroacetic acid or hydrochloric acid) to reveal a compound offormula (I.n), (I.o), or (I.p) that contains a primary or secondaryamine. If the compound of the formula (I.n), (I.o), or (I.p) contains abenzyl-amine functional group, this can be subsequently removed (e.g.,using a metal catalyst and H₂ gas), to reveal a compound of formula(I.n), (I.o), or (I.p) that contains a primary or secondary amine.

Intermediate 2.4 can be coupled with intermediate 12.1 (where -M is —B,—Sn, or —Zn, and the ketal moiety may or may not be cyclized to form aring) in the presence of a palladium catalyst and a base (e.g., cesiumcarbonate, potassium phosphate tribasic, sodium carbonate) to produceintermediate 12.2. Intermediate 12.2 may be reacted in the presence of ametal catalyst (e.g., palladium) and H₂ gas to produce Intermediate12.3. Alternatively, Intermediate 2.4 can be coupled with intermediate12.4 (where -M is —B or —Zn, and the ketal moiety may or may not becyclized to form a ring) in the presence of a palladium catalyst toproduce intermediate 12.3. Alternatively, Intermediate 2.4 can becoupled with intermediate 12.5 (where —X is —Cl, —Br, —I, OMs, —OTs,—OTf, and the ketal moiety may or may not be cyclized to form a ring) inthe presence of a palladium or nickel catalyst to produce intermediate12.3. Intermediate 12.3 may be reacted in the presence of aqueous base(e.g. potassium carbonate) to afford Intermediate 12.6. Intermediate12.6 may be reacted in the presence of acid (e.g., TFA, HCl) to producea compound of formula (I.q).

Compounds of formula (I.r) can be assembled by the combination ofcompounds of formula (I.q) with a suitable primary or secondary amine3.1, in the presence of a suitable reducing reagent (e.g., NaBH₄,Na(OAc)₃BH, Na(CN)₃BH). Compounds of formula (I.s) can be assembled bythe combination of compounds of formula (I.q) with a suitable cyclicamine 4.1, in the presence of a suitable reducing reagent (e.g., NaBH₄,Na(OAc)₃BH, Na(CN)₃BH). If the compound of the formula (I.r) or (I.s)contains a tert-butylcarbamate functional group, this can besubsequently removed by treatment with acid (e.g., trifluoroacetic acidor hydrochloric acid) to reveal a compound of formula (I.r) or (I.s)that contains a primary or secondary amine. If the compound of theformula (I.r) or (I.s) contains a benzyl-amine functional group, thiscan be subsequently removed (e.g., using a metal catalyst and H₂ gas),to reveal a compound of formula (I.r) or (I.s) that contains a primaryor secondary amine.

Intermediate 14.2 may be synthesized by reacting Intermediate 14.1 inthe presence of acid (e.g., HCl, TFA). Intermediate 14.2 may be reactedin the presence of suitable halogenating reagent (e.g., NBS, NIS, NCS)to produce intermediate 14.3, where X=I, Br, or Cl. Intermediate 14.3may be reacted in the presence of DMF-DMA and hydroxyamine-O-sulfonicacid to afford Intermediate 14.4. Intermediates of the formula 1.1.a maybe furnished by reacting Intermediate 14.4 in the presence of a suitableboron reagent (e.g. B₂Pin₂, HBPin), a suitable base (e.g. potassiumacetate, potassium propionate, triethylamine), and a suitable palladiumcatalyst.

VIII. EXAMPLES

Exemplary chemical entities of the present disclosure are provided inthe specific examples that follow. Those skilled in the art willrecognize that, to obtain the various compounds herein, startingmaterials may be suitably selected so that the ultimately desiredsubstituents will be carried through the reaction scheme with or withoutprotection as appropriate to yield the desired product. Alternatively,it may be necessary or desirable to employ, in the place of theultimately desired substituent, a suitable group that may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent. Furthermore, one of skill in the art will recognize thatthe transformations shown in the schemes below may be performed in anyorder that is compatible with the functionality of the particularpendant groups.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

Intermediates Preparation of Intermediate I-1

6,7-dihydro-5H-cyclopenta[c]pyridin-1-amine (I-1): To a solution oftert-butyl (6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)carbamate (preparedaccording to the literature procedure in WO 2015/058160, paragraph00843) (6 g, 25.6 mmol) dissolved in dioxane (50 mL) and methanol (75mL) was added hydrochloric acid (4M in dioxane, 25.6 mL, 102 mmol), andthe reaction mixture was stirred for 24 h at room temperature. Thereaction mixture was concentrated under reduced pressure, and the cruderesidue was dissolved in dichloromethane (100 mL) and 50% aqueouspotassium carbonate (20 mL). The mixture was stirred for 30 minutes atroom temperature, and the pH was checked to be >8. The layers wereseparated, and the aq. layer was extracted with dichloromethane (2×50mL). The combined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure to give the title compound.

Preparation of Intermediate I-2

4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-1-amine (I-2): To a solutionof 6,7-dihydro-5H-cyclopenta[c]pyridin-1-amine (I-1) (3.4 g, 25.3 mmol)in acetonitrile (100 mL) and dichloromethane (100 mL) cooled to 0° C.was added a solution of N-bromosuccinimide (4.51 g, 25.3 mmol) dissolvedin acetonitrile (30 mL) dropwise, and the reaction mixture was allowedto slowly warm to room temperature and stirred for 1 h. The mixture wasconcentrated, and the crude mixture was dissolved in dichloromethane(150 mL). The organic layer was washed with 50% aq. NaHCO3 (40 mL), andonce with water (40 mL). The combined aqueous layers were extracted withDCM (50 mL). The combined organic layers were dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The cruderesidue was purified by column chromatography (20-100% EtOAc in hexane)to give the title compound. ES/MS: 215.1 (M⁺).

Preparation of Intermediate I-3

6-bromo-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine(I-3): To a solution of4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-1-amine (I-2) (5.4 g, 25.3mmol) in DMF (14 mL) was added N,N-dimethylformamide dimethyl acetal(DMF-DMA) (16.6 mL, 101 mmol), and the reaction mixture was for 6 hoursat 80° C. The mixture was concentrated under reduced pressure, andmethanol (10 mL) was added to the crude mixture. The mixture was cooledto 0° C., and pyridine (3.07 mL, 38 mmol) was added, followed byhydroxylamine-O-sulfonic acid (4.3 g, 38 mmol). The mixture was stirredovernight, warming to room temperature. The precipitated product wasfiltered and saved. The filtrate was concentrated under reducedpressure, and dissolved in DCM (120 mL), EtOAc (20 mL), and sat. aq.sodium bicarbonate (50 mL). The layers were separated, and the aqueouslayer was extracted with DCM (2×50 mL). The combined organic layers werewashed with brine (40 mL), and were dried over magnesium sulfate,filtered and concentrated under reduced pressure. The crude residue waspurified by column chromatography (15-100% EtOAc in hexane) to give thetitle compound, which was combined with the precipitated product andcarried forward. ES/MS: 238.0 (M⁺). ¹H NMR (400 MHz, Methanol-d4) δ 8.94(d, J=1.1 Hz, 1H), 8.37 (s, 1H), 3.40-3.34 (m, 2H), 3.20-3.12 (m, 2H),2.41-2.30 (m, 2H).

Preparation of Intermediate I-4

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine(I-4): To a 250 mL RBF was added6-bromo-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine (I-3)(5.37 g, 22.6 mmol), Bis(pinacolato)diboron (8.59 g, 33.8 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.17 g,1.58 mmol), and potassium propionate (7.59 g, 67.7 mmol). The mixturewas dissolved in 1,4-dioxane (50 mL), and nitrogen was bubbled throughthe reaction mixture for 5 minutes. The mixture was heated at 95° C. for1 hour under nitrogen. The mixture was cooled to rt, filtered throughcelite, and concentrated under reduced pressure. The crude residue waspurified by silica gel chromatography (eluent: EtOAc/hexanes) to providethe product I-4. ES/MS: 286.2 (M+H⁺). ¹H NMR (400 MHz, Chloroform-d) δ8.83 (s, 1H), 8.32 (s, 1H), 3.30-3.18 (m, 4H), 2.28 (p, J=7.6 Hz, 2H),1.38 (s, 12H).

Preparation of Intermediate I-5

1-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-methylbutan-1-one(I-5): To a vial was added6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine(I-4) (4.66 g, 16.3 mmol), palladium acetate (0.220 g, 0.98 mmol),1,1′-bis(diphenylphosphino)ferrocene (dppf) (0.770 g, 1.39 mmol), andsodium carbonate (0.866 g, 8.17 mmol), followed by THF (50 mL), water(2.06 mL, 114 mmol) and isovaleric anhydride (4.57 mL, 22.9 mmol). Argonwas bubbled through the mixture for 4 min and the reaction mixture washeated to 60° C. for 4 h. The reaction mixture was filtered throughcelite, rinsing with EtOAc and the filtrate was concentrated underreduced pressure. The crude residue was purified by columnchromatography (10-70% EtOAc in hexane) to give the title compound.ES/MS: 244.2 (M+H⁺). ¹H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.43(s, 1H), 3.51-3.37 (m, 2H), 3.36-3.22 (m, 2H), 2.85 (d, J=6.9 Hz, 2H),2.43-2.22 (m, 3H), 1.04 (d, J=6.6 Hz, 6H).

Preparation of Intermediate I-6

di-tert-butyl1-(5-(methoxycarbonyl)-4-methylthiophen-2-yl)hydrazine-1,2-dicarboxylate(I-6): To a solution of methyl 5-bromo-3-methyl-thiophene-2-carboxylate(3.90 g, 16.6 mmol) in THF (50 mL) cooled to −40° C. was addedisopropylmagnesium bromide in 2-MeTHF (2.90 mol/L, 8.01 mL, 23.2 mmol)dropwise and the solution was stirred for 30 min at −40° C.Di-tert-butylazodicarboxylate (4.58 g, 19.9 mmol) was then added as asolution in THF (50 mL) dropwise and the reaction was stirred for 15 minat −40° C. The reaction was quenched by the addition of saturatedaqueous ammonium chloride and the mixture was extracted with DCM (3×).The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and the filtrate was concentrated under reducedpressure. The crude residue was purified by column chromatography (0-50%EtOAc in hexane) to give the title compound. ES/MS: 387.2 (M+H⁺). ¹H NMR(400 MHz, Methanol-d₄) δ 6.62 (s, 1H), 3.82 (s, 3H), 2.46 (s, 3H),1.60-1.51 (m, 18H).

Preparation of Intermediate I-7

methyl4-isopropyl-3-methyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrole-2-carboxylate(I-7): To a solution of di-tert-butyl1-(5-(methoxycarbonyl)-4-methylthiophen-2-yl)hydrazine-1,2-dicarboxylate(I-6) (5.69 g, 14.7 mmol) and p-Toluenesulfonic Acid, monohydrate (15.2g, 88.3 mmol) in 2-MeTHF (150 mL) in a 500 mL round-bottomed flask wasadded1-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-methylbutan-1-one(I-5) (3.58 g, 14.7 mmol) and the reaction mixture was heated to 90° C.for 16 h with a reflux condenser. The reaction mixture was concentratedunder reduced pressure, taken up in EtOAc and washed with sat. aq.sodium bicarbonate. The layers were separated, the aqueous layer wasextracted with EtOAc (2×) and the combined organic layers were washedwith brine, dried over sodium sulfate, filtered and the filtrate wasconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (15-100% EtOAc in hexane) to give the titlecompound. ES/MS: 395.2 (M+H⁺). ¹H NMR (400 MHz, Methanol-d4) δ 8.63 (d,J=1.1 Hz, 1H), 8.43 (s, 1H), 3.85 (s, 3H), 3.32-3.27 (m, 2H), 3.24-3.11(m, 1H), 3.00 (t, J=7.5 Hz, 2H), 2.87 (s, 3H), 2.31 (q, J=7.6 Hz, 2H),1.32 (d, J=7.1 Hz, 6H).

Preparation of Intermediate I-8

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole(I-8): To a solution of methyl4-isopropyl-3-methyl-5-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrole-2-carboxylate(I-7) (3.1 g, 7.86 mmol) in ethanol (150 mL) and water (20 mL) was addedpotassium hydroxide (2.65 g, 47.1 mmol) and the reaction mixture washeated to 90° C. for 16 h. The reaction mixture was concentrated underreduced pressure then diluted with hydrochloric acid (1.00 mol/L, 63 mL,62.9 mmol) and cooled to 0° C. for 30 minutes to facilitateprecipitation. The precipitate was collected by filtration, rinsed oncewith water, and air-dried for 1 h to give the title product. Thematerial was further dried overnight in a lyophilizer to complete thedrying process. ES/MS: 337.2 (M+H⁺).

Preparation of Intermediate I-9

tert-butyl5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-9): To a solution of5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole(I-8) (1.89 g, 5.62 mmol) in THF (150 mL) was addedN,N-dimethylpyridin-4-amine (DMAP) (0.961 g, 7.86 mmol), andtert-butoxycarbonyl tert-butyl carbonate (1.59 mg, 7.30 mmol). Themixture was stirred at rt overnight. The mixture was concentrated underreduced pressure. The crude residue product was purified by flashchromatography (eluent: EtOAc/hexanes) to provide the product. ES/MS:437.2 (M+H⁺).

Preparation of Intermediate I-10

tert-butyl2-bromo-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-10): To a solution of tert-butyl5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-9) (1.64 g, 3.76 mmol) in ACN (100 mL) and methanol (100) cooled to0° C. was added N-bromosuccinimide (0.67 g, 3.76 mmol) dissolved in ACN(30 mL) dropwise and the reaction mixture was monitored by LCMS forreaction completion. The reaction was diluted with DCM and quenched bythe addition of 10% aqueous thiosulfate and the layers separated. Theaqueous layer was extracted with DCM (2×). The combined organic extractswere washed with brine, dried over sodium sulfate, filtered and thefiltrate was concentrated under reduced pressure. The crude residue waspurified by column chromatography (0-100% EtOAc in hexane) to give thetitle compound. ES/MS: 391.1 (M⁺). ¹H NMR (400 MHz, Methanol-d4) δ 8.63(s, 1H), 8.47 (s, 1H), 7.59 (s, 1H), 3.31-3.23 (m, 2H), 2.69 (s, 3H),2.48 (s, 3H), 1.40 (dd, J=7.1, 1.0 Hz, 6H).

Preparation of Intermediate I-11

tert-butyl (1R,5S)-3-iodo-8-azabicyclo[3.2.1]octane-8-carboxylate(I-11): To a solution of tert-butyl(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 6.6mmol) in toluene (50 mL) was added triphenylphosphine (1.96 g, 7.92mmol), molecular iodine (2.01 g, 7.92 mmol) and imidazole (899 mg, 13.2mmol). The mixture was stirred at reflux overnight. The mixture wasconcentrated under reduced pressure. The crude residue product waspurified by flash chromatography (eluent: EtOAc/hexanes) to provide theproduct. ES/MS: 282.0 (M+H⁺) (mass minus tert-butyl).

Preparation of Intermediate I-12

tert-butyl (1S,4S,5S)-5-iodo-2-azabicyclo[2.2.1]heptane-2-carboxylate(I-12): Prepared analogously to I-11, substituting tert-butyl(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate withtert-butyl(1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate. ES/MS:268.0 (M+H⁺) (mass minus tert-butyl).

Preparation of Intermediate I-13

tert-butyl 2-iodo-6-azaspiro[3.4]octane-6-carboxylate (I-13): Preparedanalogously to I-11, substituting tert-butyl(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate withtert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate. ES/MS: 282.1(M+H⁺) (mass minus tert-butyl).

Preparation of Intermediate I-14

6-bromo-2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(I-14): To a solution of 7-bromo-1,3-dihydrofuro[3,4-c]pyridin-4-amine(1.5 g, 6.98 mmol) in DMF (6 mL) was added1,1-dimethoxy-N,N-dimethyl-ethanamine (4.13 mL, 27.9 mmol), and thereaction mixture was stirred for 3 hours at 100° C. The mixture wasconcentrated under reduced pressure, and methanol (5 mL) was added tothe crude mixture. The mixture was cooled to 0° C., and pyridine (0.85mL, 10.5 mmol) was added, followed by hydroxylamine-O-sulfonic acid(1.18 g, 10.5 mmol). The mixture was stirred overnight, warming to roomtemperature. The precipitated product was filtered and saved. Thefiltrate was concentrated under reduced pressure, and dissolved in DCM(60 mL), EtOAc (20 mL), and sat. aq. sodium bicarbonate (25 mL). Thelayers were separated, and the aqueous layer was extracted with DCM(2×25 mL). The combined organic layers were washed with brine (20 mL),and were dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude residue was purified by columnchromatography (15-100% EtOAc in hexane) to give the title compound,which was combined with the precipitated product and carried forward.ES/MS: 254.0 (M⁺)

Preparation of Intermediate I-15

2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(I-15): Prepared analogously to I-4, substituting6-bromo-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine (I-3)with6-bromo-2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(I-15) ES/MS: 302.2 (M+H⁺) ¹H NMR (400 MHz, Chloroform-d) δ 4.20 (s,1H), 4.08 (ddd, 1H), 3.29 (dd, 1H), 3.06 (d, 1H), 2.90-2.84 (m, 1H),2.59-2.47 (m, 1H), 2.26 (dt, 1H), 2.10 (d, 1H), 1.78 (dd, 1H), 1.46 (d,9H).

Preparation of Intermediate I-16

6-bromo-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine (I-16): Toa solution of 7-bromo-1,3-dihydrofuro[3,4-c]pyridin-4-amine (I-15) (2.0g, 9.30 mmol) in DMF (3 mL) was added N,N-dimethylformamide dimethylacetal (DMF-DMA) (3.74 mL, 27.9 mmol), and the reaction mixture wasstirred overnight at 130° C. After cooling to room temperature, thevolatiles were removed under reduced pressure to afford the intermediateimine product. To an ice-cooled, stirred solution of the crudeintermediate in methanol (20 mL) and pyridine (1.5 mL) was addedhydroxylamine-O-sulfonic acid (1.58 g, 14.0 mmol). The reaction mixturewas allowed to warm to room temperature and was stirred overnight. Thevolatiles were removed under reduced pressure, and the residue waspartitioned between sat. aq. sodium bicarbonate (50 mL) and EtOAc (50mL). The aqueous layer was further extracted with EtOAc (3×20 mL), andthe combined organic layers were washed sequentially with water (100 mL)and brine (100 mL), dried over magnesium sulfate, and concentrated underreduced pressure to yield a mixture of the desire product and thehydroxy-imine intermediate. The mixture of the product and theintermediate was re-dissolved in THF (5 mL) and to the solution T3P[(1-propanephosphonic acid cyclic anhydride) 50% in DMF] (1 mL) wasadded, and the reaction was stirred overnight at 50° C. The reactionmixture was concentrated under reduced pressure. The crude product wasdirectly purified by flash chromatography (eluent: EtOAc/hexane) toprovide the product. ES/MS: 240.0 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ 8.75(t, J=1.1 Hz, 1H), 8.36 (s, 1H), 5.59 (tt, J=2.6, 1.1 Hz, 2H), 5.27 (dd,J=4.0, 3.1 Hz, 2H).

Preparation of Intermediate I-17

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(I-17): Prepared analogously to I-4, substituting6-bromo-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine (I-3)with 6-bromo-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(I-16). ES/MS: 288.2 [M+H⁺]. ¹H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H),8.39 (s, 1H), 5.81-5.23 (m, 4H), 1.38 (s, 12H).

Preparation of Intermediate I-18

8-Bromo-4-methyl-3,5,6-triazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraene(I-18): Prepared analogously to I-2, substituting DMF-DMA with1,1-dimethoxy-N,N-dimethyl-ethanamine. ES/MS: 254.1 [M+2H⁺]. ¹H NMR (400MHz, CDCl₃) δ 8.53 (d, J=1.3 Hz, 1H), 3.41-3.32 (m, 2H), 3.10 (td,J=7.6, 1.4 Hz, 2H), 2.60 (d, J=1.0 Hz, 3H), 2.31 (p, J=7.6 Hz, 2H).

Preparation of Intermediate I-19

2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine(I-19): Prepared analogously to I-4, substituting6-bromo-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine (I-3)with8-Bromo-4-methyl-3,5,6-triazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraene(I-18). ES/MS: 300.2 [M+H⁺]

Preparation of Intermediate I-20

tert-butyl (1S,4S,5R)-5-iodo-2-azabicyclo[2.2.1]heptane-2-carboxylate(I-20): Prepared analogously to I-11, substituting tert-butyl(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate withtert-butyl(1S,4S,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate. ES/MS:268.0 (M+H⁺) (mass minus tert-butyl)¹H NMR (400 MHz, Chloroform-d) δ4.20 (s, 1H), 4.08 (ddd, 1H), 3.29 (dd, 1H), 3.06 (d, 1H), 2.90-2.84 (m,1H), 2.59-2.47 (m, 1H), 2.26 (dt, 1H), 2.10 (d, 1H), 1.78 (dd, 1H), 1.46(d, 9H).

Preparation of Intermediate I-21

di-tert-butyl1-(5-(methoxycarbonyl)thiophen-2-yl)hydrazine-1,2-dicarboxylate (I-21):The reaction was performed analogously to that of I-6 starting frommethyl 5-bromothiophene-2-carboxylate to give the title compound. ES/MS:373.2 (M+H⁺)

Preparation of Intermediate I-22

4-bromo-2,3-dihydrofuro[2,3-c]pyridin-7-amine (I-22): Preparedanalogously to I-2, substituting6,7-dihydro-5H-cyclopenta[c]pyridin-1-amine (I-1) with2,3-dihydrofuro[2,3-c]pyridin-7-amine. ES/MS: 215.0 (M⁺). 1H NMR (400MHz, Chloroform-d) δ 7.71 (s, 1H), 4.68 (t, J=9.0 Hz, 2H), 3.26 (t,J=9.0 Hz, 2H).

Preparation of Intermediate I-23

6-bromo-7,8-dihydrofuro[2,3-c][1,2,4]triazolo[1,5-a]pyridine (I-23): Toa solution of 4-bromo-2,3-dihydrofuro[2,3-c]pyridin-7-amine (I-22) (1.1g, 5.12 mmol) in DMF (3 mL) was added N,N-dimethylformamide dimethylacetal (DMF-DMA) (3.35 mL, 20.5 mmol), and the reaction mixture wasstirred for 6 hours at 80° C. The mixture was concentrated under reducedpressure, and methanol (3 mL) was added to the crude mixture. Themixture was cooled to 0° C., and pyridine (0.62 mL, 7.67 mmol) wasadded, followed by hydroxylamine-O-sulfonic acid (0.87 g, 7.67 mmol).The mixture was stirred overnight, warming to room temperature. Theprecipitated material was filtered. The precipitate was added to a 50 mLRBF, and THF (15 mL) was added. 1-Propanephosphonic acid (T3P) (50%solution in 2-MeTHF, 3.3 mL) was added dropwise, and the mixture wasstirred overnight at 55° C. The mixture was diluted with EtOAc (50 mL),and the organic layer was washed with sat. aq. NaHCO₃ (20 mL) and brine(10 mL), and then the organic layer was dried over magnesium sulfate,filtered and concentrated under reduced pressure. The crude residue waspurified by column chromatography (15-100% EtOAc in hexane) to give thetitle compound. ES/MS: 240.0 (M⁺)

Preparation of Intermediate I-24

tert-butyl 2-iodo-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (I-24):Prepared analogously to I-11, substituting tert-butyl(1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate withtert-butyl 2-hydroxy-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate. ES/MS:298.0 (M+H⁺) (mass minus tert-butyl)

Preparation of Intermediate I-25

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydrofuro[2,3-c][1,2,4]triazolo[1,5-a]pyridine(I-25): Prepared analogously to I-4, substituting6-bromo-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine (I-3)with 6-bromo-7,8-dihydrofuro[2,3-c][1,2,4]triazolo[1,5-a]pyridine(I-23). ES/MS: 288.1 (M+H⁺)

Preparation of Intermediate I-26

tert-butyl2-bromo-5-(7,8-dihydrofuro[2,3-c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-26): Prepared analogously to I-5, I-7, I-8, I-9, and I-10,substituting6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridine(I-4) with6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydrofuro[2,3-c][1,2,4]triazolo[1,5-a]pyridine(I-25). ES/MS: 517.1 (M⁺) 1H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 1H),8.21 (s, 1H), 5.03-4.64 (m, 2H), 3.13 (qdd, J=15.7, 10.1, 8.1 Hz, 2H),2.97 (p, J=7.1 Hz, 1H), 2.48 (s, 3H), 1.41 (s, 9H), 1.28-1.25 (m, 3H),1.23 (d, J=7.1 Hz, 3H).

Preparation of Intermediate I-27

methyl5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-2-carboxylate(I-27): Prepared analogously to I-7, substituting di-tert-butyl1-(5-(methoxycarbonyl)-4-methylthiophen-2-yl)hydrazine-1,2-dicarboxylate(I-6) with di-tert-butyl1-(5-(methoxycarbonyl)thiophen-2-yl)hydrazine-1,2-dicarboxylate (I-21).ES/MS: 381.1 (M+H⁺)

Preparation of Intermediate I-28

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-2-carboxylicacid (I-28): To a solution of methyl5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-2-carboxylate(1 g, 2.63 mmol) (I-27) in THF (20 mL) was added lithium hydroxidemonohydrate (221 mg, 5.26 mmol) (dissolved in 17 mL water) and thereaction mixture was stirred for 16 h at 70° C. The reaction mixture wasconcentrated under reduced pressure, then diluted with hydrochloric acid(1.00 mol/L, 6.57 mL, 6.57 mmol), cooled to 0° C., and the precipitatewas collected by filtration to give the title compound which was useddirectly in the next step. ES/MS: 367.1 (M+H⁺)

Preparation of Intermediate I-29

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole(I-29): To a solution of5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-2-carboxylicacid (I-28) (500 mg, 1.36 mmol) in DMA (3 mL) was added DBU (0.611 mL,4.09 mmol), and the resulting reaction mixture was stirred at 150° C.for 2 h. The reaction mixture was allowed to cool to room temperature,diluted with EtOAc (60 mL) and extracted with brine (2×20 mL). Theaqueous layers were combined and extracted with EtOAc (60 mL). Thecombined organic layer was dried over Na₂SO₄, concentrated under reducedpressure, and purified by flash column chromatography ES/MS: 323.1(M+H⁺).

Preparation of Intermediate I-30

tert-butyl5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-30): Prepared analogously to I-9, substituting5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole(I-8) with5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole(I-29). ES/MS: 423.2 (M+H⁺)

Preparation of Intermediate I-31

tert-butyl2-bromo-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-31): Prepared analogously to I-10, substituting tert-butyl5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-9) with tert-butyl5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-30). ES/MS: 501.1 (M⁺)

Preparation of Intermediate I-32

5-ethyl 2-methyl4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-2,5-dicarboxylate: To asolution of di-tert-butyl1-(5-(methoxycarbonyl)-4-methylthiophen-2-yl)hydrazine-1,2-dicarboxylate(I-6) (32.2 g, 83 mmol) and p-Toluenesulfonic Acid, monohydrate (66.1 g,348 mmol) in a 500 mL round-bottomed flask in 2-butanol (140 mL) wasadded ethyl 4-methyl-2-oxo-pentanoate (11 g, 69.5 mmol) and the reactionmixture was heated to 90° C. for 16 h with a reflux condenser. Thereaction mixture was concentrated under reduced pressure, taken up inEtOAc and water. The layers were separated, the aqueous layer wasextracted with EtOAc (2×) and the combined organic layers were washedwith brine, dried over sodium sulfate, filtered and the filtrate wasconcentrated under reduced pressure. The crude product was used for thenext step. ES/MS: 310.0 (M+H⁺)

4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-2,5-dicarboxylic acid: To asolution of 5-ethyl 2-methyl4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-2,5-dicarboxylate (21 g,67.9 mmol) in ethanol (150 mL) was added potassium hydroxide (339 mL, 1Maq.) and the reaction mixture was heated to 100° C. for 24 h. Thereaction mixture was concentrated under reduced pressure then dilutedwith hydrochloric acid (339 mL, 1M aw.) and poured onto a brinesolution. The product was extracted from the aqueous phase with EtOAc(2×) and the combined organic layers were washed with brine, dried oversodium sulfate, filtered and the filtrate was concentrated under reducedpressure. The crude product was used for the next step. ES/MS: 268.0(M+H⁺)

4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole: To a solution of4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-2,5-dicarboxylic acid (18.1g, 67.7 mmol) in DMA (120 mL) was added DBU (30.3 mL, 203 mmol), and theresulting reaction mixture was stirred at 150° C. for 2 h. The reactionmixture was allowed to cool to room temperature, diluted with EtOAc (30mL) and extracted with brine (2×20 mL). The aqueous layers were combinedand extracted with EtOAc (30 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The crude residueproduct was purified by flash chromatography (eluent: EtOAc/hexanes) toprovide the product. ES/MS: 180.1 (M+H⁺)

tert-butyl 4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate:To a solution of 4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole. (12.1 g,67.5 mmol) in THF (150 mL) was added N,N-dimethylpyridin-4-amine (DMAP)(2.0 g, 16.9 mmol), triethylamine (9.41 mL, 67.5 mmol), andtert-butoxycarbonyl tert-butyl carbonate (15.5 g, 70.9 mmol). Themixture was stirred at rt for 16 h. The mixture was concentrated underreduced pressure. The crude residue product was purified by flashchromatography (eluent: EtOAc/hexanes) to provide the product. 1H NMR(400 MHz, Chloroform-d) δ 7.00 (s, 1H), 6.57 (s, 1H), 3.14 (pd, J=6.8,1.0 Hz, 1H), 2.43 (s, 3H), 1.67 (s, 9H), 1.32 (d, J=6.8 Hz, 6H).

tert-butyl2-bromo-4-isopropyl-3-methyl-thieno[2,3-b]pyrrole-6-carboxylate(I-32):To an solution of tert-butyl4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate (7.02 g, 25.1mmol) in acetonitrile (70.1 mL) at 0° C. was added NBS (4.47 g, 25.1mmol) dissolved in acetonitrile (10 mL) dropwise until LCMS showedcompletion of reaction. The reaction mixture was diluted with EtOAc (150mL) and the resultant mixture was extracted with aq. sodium thiosulfatesolution (30 mL). The organic layer was then successively washed withwater (2×30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, andevaporated under reduced pressure and the crude residue was purified bycolumn chromatography (eluent: EtOAc in hexane) to give the product.ES/MS: 302.0 (M⁺) (mass minus tert-butyl) ¹H NMR (400 MHz, DMSO-d₆) δ7.18 (s, 1H), 3.21-2.97 (m, 1H), 2.32 (s, 3H), 1.59 (s, 9H), 1.24 (d,J=6.8 Hz, 6H).

Preparation of Intermediate I-33

tert-butyl2-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-4-isopropyl-3-methyl-thieno[2,3-b]pyrrole-6-carboxylate:To tert-butyl2-bromo-4-isopropyl-3-methyl-thieno[2,3-b]pyrrole-6-carboxylate (I-32)(4.1 g, 11.4 mmol) in 10:1 dioxane (100 ml) and water (10 mL) was addedtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(4.6 g, 14.8 mmol), XPhos Pd G3 (859 mg, 1.1 mmol) and cesium carbonate(11.1 g, 34.2 mmol). The reaction mixture was degassed with argon, andheated to 110° C. for 2 hours. The reaction mixture was diluted withEtOAc (150 mL) and the resultant mixture was extracted with aq. sodiumthiosulfate solution (30 mL). The organic layer was then washed withwater (2×30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, andevaporated under reduced pressure. The crude residue was purified bycolumn chromatography (eluent: EtOAc in hexane) to give the product.ES/MS: 461.2 (M+H⁺)

tert-butyl2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate:To a solution of tert-butyl2-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-4-isopropyl-3-methyl-thieno[2,3-b]pyrrole-6-carboxylate(4.2 g, 9.12 mmol) in ethyl acetate (25 mL) was added palladium oncarbon 10 wt. % (10.0%, 970 mg, 9.12 mmol) and the reaction mixture wasstirred at room temp for 24 h under an atmosphere of hydrogen. Thereaction mixture was subsequently degassed with argon, diluted withEtOAc, and filtered through celite, rinsing with EtOAc. The filtrate wasconcentrated under reduced pressure to give the product which was useddirectly in the next step. ES/MS: 463.3 (M+H⁺)

tert-butyl4-(4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)piperidine-1-carboxylate(I-33): To tert-butyl2-(1-tert-butoxycarbonyl-4-piperidyl)-4-isopropyl-3-methyl-thieno[2,3-b]pyrrole-6-carboxylate(4.2 g, 9.1 mmol) in a 1:1:1 mixture of EtOH/THF/water (50 mL) was addedLiOH (1.4 g, 54.7 mmol) and the reaction mixture was stirred for 16 h at80° C. The reaction mixture was diluted with EtOAc (150 mL) and theorganic layer was then successively washed with water (2×50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered, and evaporated under reducedpressure to provide the product. ES/MS: 363.3 (M+H⁺)

Preparation of Intermediate I-34

tert-butyl2-((1S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-5-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate:To dried vial was added tert-butyl2-bromo-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-32) (250 mg, 0.7 mmol), tert-butyl(1S,4S,5R)-5-iodo-2-azabicyclo[2.2.1]heptane-2-carboxylate (I-20) (451mg, 1.4 mmol), tetrabutylammonium iodide (TBAI) (309 mg, 0.837 mmol),Ni(dtbbpy)(H₂O)₄Cl₂ (32.8 mg, 0.07 mmol), and zinc dust (272 mg, 4.19mmol). Dry DMA (2.5 mL) was added, and the mixture was degassed for 1minute with argon. The vial was sealed, and the reaction was stirred at70° C. for 16 h. Afterward, the reaction was cooled, and the crudemixture was purified directly by silica chromatography (eluent:EtOAc/hexanes) to provide the product.

tert-butyl(1S,4R,5R)-5-(4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(I-34): To a solution of tert-butyl2-((1S,4R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-5-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(320 mg, 0.67 mmol) in THF (1 mL) and MeOH (2 mL) was added LiOHmonohydrate (100 mg, 2.38 mmol) (dissolved in 1 mL water) and thereaction mixture was stirred for 6 h at 90° C. The reaction mixture wasdiluted with EtOAc (50 mL) and the organic layer was then successivelywashed with water (15 mL) and brine (5 mL), dried over MgSO₄, filtered,and evaporated under reduced pressure to provide the product. ES/MS:375.2 (M+H⁺)

Preparation of Intermediate I-35

tert-butyl(1R,3s,5S)-3-(4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate(I-35): Prepared analogously to I-34, substituting tert-butyl(1S,4S,5R)-5-iodo-2-azabicyclo[2.2.1]heptane-2-carboxylate (I-20) withtert-butyl (1R,5S)-3-iodo-8-azabicyclo[3.2.1]octane-8-carboxylate(I-11). ES/MS: 389.2 (M+H⁺)

Preparation of Intermediate I-36

4-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)cyclohexan-1-one(I-36): To dried vial was added tert-butyl2-bromo-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-10) (200 mg, 0.39 mmol), 8-iodo-1,4-dioxaspiro[4.5]decane (208 mg,0.78 mmol), tetrabutylammonium iodide (TBAI) (172 mg, 0.47 mmol),Ni(dtbbpy)(H₂O)₄Cl₂ (721.9 mg, 0.047 mmol) and zinc dust (151 mg, 2.33mmol). Dry DMA (2 mL) was added, and the mixture was degassed for 1minute with argon. The vial was sealed, and the reaction was stirred at70° C. for 16 h. Afterward, the reaction was cooled, and the crudemixture was purified directly by silica chromatography (eluent:EtOAc/hexanes). To a solution of the purified product in MeOH (1 mL) andTHF (1 mL), LiOH (excess) was added and the resulting reaction mixturewas stirred at 80° C. for 3 hr. The reaction mixture was cooled down toroom temperature, diluted with EtOAc (30 mL) and water (5 mL). Thelayers were separated, and the organic layer was washed once with brine(5 mL). The organic layer was dried over MgSO₄, filtered andconcentrated. To a solution of the crude product in DCM (2 mL), 4N HClin dioxane (5 mL) and 1N aq. HCl (0.1 mL) was added and stirred at roomtemperature for 2 hr. The reaction mixture was diluted with DCM (20 mL),washed sequentially with aq. NaHCO₃ (2×10 mL), water (20 mL), brine (10mL), dried over NaSO₄ and concentrated under reduced pressure to providethe title compound. ES/MS: 433.1 (M+H⁺)

Final Procedures Procedure 1, Example 1

tert-butyl4-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)piperidine-1-carboxylate:To a dried vial was added tert-butyl2-bromo-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-10) (113 mg, 0.219 mmol tert-butyl 4-iodopiperidine-1-carboxylate(102 mg, 0.329 mmol), tetrabutylammonium iodide (TBAI) (12.1 mg, 0.033mmol), Ni(dtbbpy)(H₂O)₄Cl₂ (7.2 mg, 0.0153 mmol), zinc dust (72 mg, 1.1mmol), and 4 Angstrom molecular sieves (40 mg). Dry DMA (1.0 mL) wereadded, and the mixture was degassed for 1 minute with argon. The vialwas sealed, and the reaction was stirred at 70° C. for 16 h. Afterward,the reaction was cooled, and the crude mixture was purified directly bysilica chromatography (eluent: EtOAc/hexanes). The purified material wasdissolved in MeOH (1.5 mL) and potassium carbonate (sat. aq., 0.25 mL)was added. The mixture was stirred at 40 degrees overnight. LCMSindicated removal of the Boc group, and the mixture was diluted withEtOAc (30 mL) and water (5 mL). The layers were separated, and theorganic layer was washed with brine (5 mL). The organic layer was driedover MgSO₄, filtered, and concentrated under reduced pressure to affordthe product. ES/MS: 520.3 (M+H⁺).

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrole:To a vial with tert-butyl4-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)piperidine-1-carboxylate(90 mg, 0.173 mmol) was added 1,4-dioxane (0.25 mL) and methanol (0.25mL). HCl (4M in dioxane, 0.52 mL, 2.08 mmol) was added, and the mixturewas stirred for 3 hours at rt. LCMS indicated reaction completion, andthe volatiles were evaporated under reduced pressure to isolate the HClsalt. To the mixture was added acetonitrile (0.5 mL), water (0.2 mL),and TFA (0.1 mL), and the mixture was filtered through an acrodiscbefore purification by RP-HPLC (0.1% TFA-ACN in 0.1% TFA Water, Column:Gemini 5 uM, NX-C18 110 Angstrom, 250×21.2 mm) to give the titlecompound Example 1. ES/MS: 420.2 (M+H⁺). ¹H NMR (400 MHz, Methanol-d4) δ8.56 (s, 1H), 8.44 (s, 1H), 3.58-3.38 (m, 5H), 3.28-3.07 (m, 3H), 3.01(t, J=7.5 Hz, 2H), 2.48 (s, 3H), 2.31 (p, J=7.7 Hz, 2H), 2.20 (d, J=14.4Hz, 2H), 1.98-1.82 (m, 2H), 1.32 (d, J=7.1 Hz, 6H).

The following Examples were made in an analogous fashion according toProcedure 1 and are shown below in Table 1. To prepare the belowExamples, different reagents/starting materials were used than some ofthose described in Procedure 1 and are noted in the last column of Table1—“Changes to Procedure 1: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of Procedure 1 were replaced with thedifferent reagents/starting materials noted below.

TABLE 1 Changes to Procedure 1: Different ES/ Reagents/ Ex- MS Startingample Structure m/z ¹H-NMR Materials 2

446.3 ¹H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.45 (s, 1H), 4.13(s, 2H), 3.68 (tt, J = 11.8, 6.2 Hz, 1H), 3.42-3.35 (m, 2H), 3.18-3.08(m, 1H), 3.00 (t, J = 7.5 Hz, 2H), 2.49 (s, 3H), 2.39-2.15 (m, 6H), 2.08(dd, J = 14.9, 4.5 Hz, 4H), 1.31 (d, J = 7.1 Hz, 6H). I-11 3

432.2 ¹H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.45 (s, 1H), 4.22(s, 1H), 3.61-3.46 (m, 1H), 3.30- 3.21 (m, 3H), 3.17-3.07 (m, 1H), 3.00(t, J = 7.5 Hz, 2H), 2.79 (s, 1H), 2.48 (s, 3H), 2.48-2.39 (m, 1H), 2.31(td, J = 14.1, 13.1, 6.8 Hz, 4H), 1.98 (dt, J = 14.8, 3.5 Hz, 1H), 1.82(d, J = 11.8 Hz, 1H), 1.32 (dd, J = 7.1, 1.2 Hz, 6H). I-12 4

446.3 ¹H NMR (400 MHz, MeOD) δ 8.56 (s, 1H), 8.46 (s, 1H), 3.95 (dq, J =13.3, 8.8 Hz, 1H), 3.47 (s, 1H), 3.38 (t, J = 7.1 Hz, 1H), 3.33 (dq, J =4.0, 2.0 Hz, 2H), 3.25 (s, 1H), 3.15-2.97 (m, 3H), 2.69-2.51 (m, 2H),2.39 (d, J = 2.5 Hz, 3H), 2.30 (ddd, J = 10.5, 7.9, 4.9 Hz, 5H), 2.11(t, J = 7.5 Hz, 1H), 1.31 (d, J = 7.1 Hz, 6H). I-13

tert-butyl2-(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate:To a dried vial was added tert-butyl2-bromo-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-10) (125 mg, 0.242 mmol), tert-butyl6-(trifluoroboraneyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate,potassium salt (118 mg, 0.388 mmol), CataCXium A Pd G3 (17.7 mg, 0.024mmol), cesium carbonate (237 mg, 0.727 mmol). Toluene (6.0 mL) and water(0.6 mL) were added, and the mixture was degassed for 4 minutes withargon. The vial was sealed, and the reaction was stirred at 90° C. for18 h. Afterward, the reaction was cooled, and the crude mixture wasfiltered through celite, rinsing with EtOAc. The mixture wasconcentrated under reduced pressure, and the crude residue was purifieddirectly by silica chromatography (eluent: EtOAc/hexanes) to afford theproduct. ES/MS: 632.4 (M+H⁺)

2-(3-azabicyclo[4.1.0]heptan-6-yl)-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole(Example 5): To a vial with tert-butyl2-(3-(tert-butoxycarbonyl)-3-azabicyclo[4.1.0]heptan-6-yl)-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(160 mg, 0.253 mmol) was added dichloromethane (4 mL). Trifluoroaceticacid (1 mL) was added, and the mixture was stirred at rt. LCMS indicatedreaction completion, and the volatiles were evaporated under reducedpressure. To the mixture was added acetonitrile (0.5 mL), water (0.2mL), and the mixture was filtered through an acrodisc beforepurification by RP-HPLC (0.1% TFA-ACN in 0.1% TFA Water, Column: Gemini5 uM, NX-C18 110 Angstrom, 250×21.2 mm) to give the title compoundExample 5. ES/MS: 432.2 (M+H⁺). ¹H NMR (400 MHz, MeOD) δ 8.56 (s, 1H),8.46 (s, 1H), 3.83 (dd, J=13.6, 7.3 Hz, 1H), 3.22 (dt, J=13.2, 5.4 Hz,1H), 3.10 (p, J=7.1 Hz, 2H), 2.98 (dt, J=17.4, 8.1 Hz, 3H), 2.55 (s,3H), 2.48-2.25 (m, 5H), 1.73-1.67 (m, 1H), 1.39 (dd, J=9.2, 5.3 Hz, 1H),1.31 (dd, J=7.1, 1.3 Hz, 6H), 1.23 (t, J=5.5 Hz, 1H).

Procedure 3, Example 6

2-(4-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)piperidin-1-yl)acetamide(Example 6): To a solution of5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrole(HCl salt) (Example 1) (43 mg, 0.094 mmol) in 1,2-dichloroethane (2 mL)was added 2-bromoacetamide (15.6 mg, 0.113 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.056 mL, 0.38 mmol). The mixturewas stirred overnight at rt. To the mixture was added 0.2 mL TFA, andthe DCE was subsequently removed under reduced pressure. Acetonitrile(0.5 mL), DMSO (0.2 mL) and water (0.2 mL) were added, and the mixturewas filtered through an acrodisc before purification by RP-HPLC (0.1%TFA-ACN in 0.1% TFA Water, Column: Gemini 5 uM, NX-C18 110 Angstrom,250×21.2 mm) to give the title compound Example 6. ES/MS: 477.3 (M+H⁺).¹H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.46 (s, 1H), 3.99 (s,2H), 3.74 (d, J=12.1 Hz, 2H), 3.62-3.37 (m, 3H), 3.30-3.19 (m, 3H),3.19-3.08 (m, 2H), 3.01 (t, J=7.5 Hz, 2H), 2.49 (s, 3H), 2.32 (p, J=7.5Hz, 2H), 2.23 (d, J=14.1 Hz, 2H), 2.09 (q, J=13.2 Hz, 2H), 1.32 (d,J=7.0 Hz, 6H).

The following Examples were made in an analogous fashion according toProcedure 3 and are shown below in Table 2. To prepare the belowExamples, different reagents/starting materials were used than some ofthose described in Procedure 3 and are noted in the last column of Table2—“Changes to Procedure 3: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of Procedure 3 were replaced with thedifferent reagents/starting materials noted below.

TABLE 2 Changes to Procedure 3: Different Ex- ES/ Reagents/ am- MSStarting ple Structure m/z ¹H-NMR Materials 7

503.3 ¹H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.46 (s, 1H), 4.14(s, 2H), 3.89 (s, 2H), 3.74 (dq, J = 12.0, 5.8 Hz, 1H), 3.38-3.34 (m,2H), 3.18-3.07 (m, 1H), 3.01 (t, J = 7.5 Hz, 2H), 2.50 (s, 3H),2.45-2.23 (m, 8H), 2.18 (d, J = 14.8 Hz, 2H), 1.31 (d, J = 7.1 Hz, 6H).Example 2 8

489.3 ¹H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.46 (s, 1H),4.35-3.96 (m, 3H), 3.76 (dd, J = 25.5, 9.5 Hz, 1H), 3.67-3.46 (m, 1H),3.21-3.05 (m, 3H), 3.01 (t, J = 7.5 Hz, 2H), 2.86- 2.56 (m, 3H), 2.49(d, J = 4.2 Hz, 3H), 2.40-2.20 (m, 4H), 2.17-1.94 (m, 2H), 1.32 (d, J =7.1 Hz, 6H). Example 3 9

503.3 ¹H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.48 (s, 1H), 4.20-3.54 (m,6H), 3.17-2.91 (m, 4H), 2.85-2.10 (m, 13H), 1.31 (d, J = 7.1 Hz, 6H).Example 4 10

489.3 ¹H NMR (400 MHz, MeOD) δ 10.77 (s, 1H), 8.56 (s, 1H), 8.46 (s,1H), 4.10 (s, 2H), 3.10 (p, J = 7.1 Hz, 2H), 3.00 (t, J = 7.5 Hz, 3H),2.55 (s, 5H), 2.31 (p, J = 7.6 Hz, 3H), 1.76 (d, J = 7.1 Hz, 1H), 1.42(s, 1H), 1.31 (dd, J = 7.2, 2.8 Hz, 8H). Example 5

Procedure 4, Example 11

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(1-(piperazin-1-ylsulfonyl)piperidin-4-yl)-6H-thieno[2,3-b]pyrrole(Example 11): To a solution of5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrole(HCl salt) (Example 1) (10 mg, 0.022 mmol) in 1,2-dichloroethane (2 mL)was added tert-butyl 4-(chlorosulfonyl)piperazine-1-carboxylate (31 mg,0.11 mmol) and N,N-diisopropylethylamine (0.02 mL, 0.11 mmol). Themixture was stirred 2 hr at rt. To the mixture was added 0.5 mL TFA, andthe DCE was subsequently removed under reduced pressure. Acetonitrile(1.5 mL) and water (0.5 mL) were added, and the mixture was filteredthrough an acrodisc before purification by RP-HPLC (0.1% TFA-ACN in 0.1%TFA Water, Column: Gemini 5 uM, NX-C18 110 Angstrom, 250×21.2 mm) togive the title compound Example 11. ES/MS: 568.2 (M+H⁺). ¹H NMR (400MHz, Methanol-d4) δ 10.71 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 3.86 (d,2H), 3.55-3.48 (m, 6H), 3.40-3.35 (m, 5H), 3.15 (dt, 2H), 3.09 (d, 1H),3.01 (t, 2H), 2.46 (s, 3H), 2.32 (q, 2H), 2.03 (d, 2H), 1.80-1.67 (m,1H), 1.31 (d, 6H).

Procedure 5, Example 12

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-6H-thieno[2,3-b]pyrrole(Example 12): To a vial with5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrole(HCl salt) (Example 1) (10 mg, 0.022 mmol) in 1,2-dichloroethane (1 mL)was added 3-methyloxetane-3-carbaldehyde (4 mg, 0.044 mmol),N,N-diisopropylethylamine (0.008 mL, 0.044 mmol), and acetic acid (1drop). The mixture was stirred 2 hr at rt. To the mixture wassubsequently added sodium triacetoxyborohydride (STAB) (14 mg, 0.066mmol), and the mixture was stirred overnight at rt. To the mixture wasadded 0.1 mL TFA, and the DCE was subsequently removed under reducedpressure. Acetonitrile (1.5 mL) and water (0.5 mL) were added, and themixture was filtered through an acrodisc before purification by RP-HPLC(0.1% TFA-ACN in 0.1% TFA Water, Column: Gemini 5 uM, NX-C18 110Angstrom, 250×21.2 mm) to give the title compound Example 12. ES/MS:504.3 (M+H⁺). ¹H NMR (400 MHz, Methanol-d4) 10.78 (s, 1H), 8.56 (s, 1H),8.44 (s, 1H), 4.65 (d, 2H), 4.44 (d, 2H), 3.56 (s, 2H), 3.50 (p, 1H),3.47 (s, 2H), 3.45-3.38 (m, 1H), 3.18-3.08 (m, 2H), 3.00 (t, 2H), 2.49(s, 3H), 2.31 (p, 2H), 2.23 (d, 2H), 2.11-1.96 (m, 2H), 1.61 (s, 3H),1.45-1.37 (m, 1H), 1.31 (d, 6H).

The following Examples were made in an analogous fashion according toProcedure 5 and are shown below in Table 3. To prepare the belowExamples, different reagents/starting materials were used than some ofthose described in Procedure 5 and are noted in the last column of Table3—“Changes to Procedure 5: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of Procedure 5 were replaced with thedifferent reagents/starting materials noted below.

TABLE 3 Changes to Procedure 5: Different Ex- Reagents/ am- ES/MSStarting ple Structure m/z ¹H-NMR Materials 13

514.3 ¹H NMR (400 MHz, Methanol-d4) δ 10.77 (s, 1H), 8.56 (s, 1H), 8.46(s, 1H), 7.72 (d, 1H), 6.49 (d, 1H), 4.35 (s, 2H), 3.97 (s, 3H), 3.67(d, 2H), 3.50 (p, 1H), 3.45-3.38 (m, 1H), 3.27-3.17 (m, 1H), 3.17-3.05(m, 1H), 3.00 (t, 2H), 2.47 (s, 3H), 2.31 (p, 2H), 2.23 (d, 2H), 2.03-1.86 (m, 2H), 1.31 (d, 6H). 1- methyl- pyrazole- 3- carbaldehyde

Procedure 6, Example 14

(R)-(4-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)piperidin-1-yl)(morpholin-3-yl)methanone(Example 14): To a vial with5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrole(HCl salt) (Example 1) (15 mg, 0.033 mmol) in 1,2-dichloroethane (2 mL)was added (R)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (11mg, 0.049 mmol),2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (19 mg, 0.049 mmol),N,N-diisopropylethylamine (0.02 mL, 0.099 mmol). The mixture was stirred5 hr at rt. To the mixture was added TFA (0.5 mL), and the mixture wasstirred 2 hr at rt. LCMS indicated removal of the Boc group. The crudemixture was concentrated under reduced pressure, and acetonitrile (1.5mL) and water (0.5 mL) were added. The mixture was filtered through anacrodisc before purification by RP-HPLC (0.1% TFA-ACN in 0.1% TFA Water,Column: Gemini 5 uM, NX-C18 110 Angstrom, 250×21.2 mm) to give the titlecompound Example 14. ES/MS: 533.3 (M+H⁺). ¹H NMR (400 MHz, Methanol-d4)δ 10.71 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 4.72 (dd, 1H), 4.65 (d,2H), 4.28 (dd, 1H), 4.06 (t, 2H), 3.86-3.75 (m, 1H), 3.74-3.56 (m, 1H),3.42-3.36 (m, 2H), 3.18-3.07 (m, 1H), 3.01 (t, 2H), 2.90 (t, 1H), 2.48(s, 3H), 2.31 (p, 2H), 2.21-2.01 (m, 3H), 1.79-1.51 (m, 2H), 1.32 (d,7H).

The following Examples were made in an analogous fashion according toProcedure 6 and are shown below in Table 4. To prepare the belowExamples, different reagents/starting materials were used than some ofthose described in Procedure 6 and are noted in the last column of Table4—“Changes to Procedure 6: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of Procedure 6 were replaced with thedifferent reagents/starting materials noted below.

TABLE 4 Changes to Procedure 6: Different Ex- ES/ Reagents/ am- MSStarting ple Structure m/z ¹H-NMR Materials 15

533.3 ¹H NMR (400 MHz, Methanol-d₄) δ 8.56 (s, 1H), 8.46 (s, 1H), 4.72(dd, 1H), 4.65 (d, 1H), 4.28 (dd, 1H), 4.06 (t, 2H), 3.85-3.75 (m, 1H),3.74-3.66 (m, 1H), 3.66-3.56 (m, 1H), 3.50 (p, 1H), 3.44-3.37 (m, 1H),3.37-3.35 (m, 4H), 3.17- 3.08 (m, 1H), 3.01 (t, 2H), 2.90 (t, 1H), 2.48(s, 3H), 2.31 (p, 2H), 2.21-2.01 (m, 2H), 1.78-1.52 (m, 2H), 1.32 (d,6H). (R)-4- (tert- butoxy- carbonyl) morpholine- 3- carboxylic acid 16

535.3 ¹H NMR (400 MHz, Methanol-d4) δ 10.72 (d, 1H), 8.56 (s, 1H), 8.46(s, 1H), 5.47 (dd, 1H), 4.67 (d, 1H), 3.92-3.78 (m, 2H), 3.61-3.53 (m,1H), 3.50 (dd, 1H), 3.47-3.37 (m, 1H), 3.17-3.07 (m, 1H), 3.05-2.96 (m,2H), 2.92-2.78 (m, 1H), 2.48 (s 3H), 2.46-2.36 (m, 1H), 2.31 (p, 2H),2.07 (d, 2H), 1.79-1.58 (m, 2H), 1.32 (d, 6H). (2R,4R)- 1-tert- butoxy-carbonyl- 4- fluoro- pyrrolidine- 2- carboxylic acid 17

535.3 ¹H NMR (400 MHz, Methanol-d4) δ 10.72 (d, 1H), 8.56 (s, 1H), 8.47(s, 1H), 5.54 (dd, 1H), 5.08-4.92 (m, 1H), 4.67 (d, 1H), 3.99 (d, 1H),3.80-3.68 (m, 1H), 3.68-3.62 (m, 1H), 3.61-3.53 (m, 1H), 3.50 (p, 1H),3.43-3.36 (m, 1H), 3.17-3.07 (m, 1H), 3.05-2.98 (m, 2H), 2.98- 2.87 (m,1H), 2.48 (s, 3H), 2.31 (p, 2H), 2.12-2.01 (m, 2H), 1.82- 1.68 (m, 1H),1.69-1.53 (m, 2H), (2R,4S)- 1-tert- butoxy- carbonyl- 4-fluoro-pyrrolidine- 2- carboxylic acid 1.32 (d, 6H). 18

547.3 ¹H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.46 (s, 1H), 4.75(dd, 1H), 4.72-4.60 (m, 2H), 4.20 (d, 1H), 3.89 (d, 1H), 3.68 (d, 1H),3.46-3.35 (m, 3H), 3.18-3.07 (m, 1H), 3.01 (t, 2H), 2.98-2.89 (m, 1H),2.82-2.68 (m, 1H), 2.48 (s, 3H), 2.31 (p, 2H), 2.21- 2.02 (m, 4H),1.76-1.54 (m, 1H), 1.32 (d, 6H). (2R,4R)- 1-tert- butoxy- carbonyl- 4-methoxy- pyrrolidine- 2- carboxylic acid 19

547.3 ¹H NMR (400 MHz, Methanol-d4) δ 10.71 (d, 1H), 8.56 (s, 1H), 8.46(s, 1H), 4.86-4.74 (m, 2H), 4.67 (d, 1H), 4.26 (dt, 1H), 3.97 (d, 1H),3.55 (dd, 1H), 3.41 (d, 4H), 3.39 (d, 1H), 3.18-3.07 (m, 1H), 3.01 (t,2H), 2.98-2.87 (m, 1H), 2.85- 2.71 (m, 1H), 2.48 (s, 3H), 2.31 (p, 2H),2.17-1.95 (m, 1H), 1.63 (td, 1H), 1.32 (d, 6H). (2R,4S)- 1-tert- butoxy-carbonyl- 4-methoxy- pyrrolidine- 2- carboxylic acid 20

573.4 ¹H NMR (400 MHz, Methanol-d4) δ 8.59 (s, 1H), 8.51 (s, 1H), 4.59(d, 2H), 3.72 (t, 4H), 3.53-3.47 (m, 1H), 3.45-3.36 (m, 1H), 3.19- 3.08(m, 2H), 3.03 (t, 2H), 2.69 (s, 4H), 2.48 (s, 3H), 2.32 (p, 2H), 2.04(d, 2H), 1.67 (d, 2H), 1.32 (d, 6H), 1.12 (s, 2H), 0.94 (s, 2H). 1-morpho- lino- cyclo- propane- 1- carboxylic acid hydro- chloride

Procedure 7, Example 21

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-2-(4-(piperazin-1-yl)phenyl)-6H-thieno[2,3-b]pyrrole(Example 21): To a vial was added tert-butyl2-bromo-5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate(I-10) (50 mg, 0.097 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(45.2 mg, 0.116 mmol), cesium carbonate (95 mg, 0.291 mmol), and XPhosPd G3 (7.3 mg, 0.0097 mmol). Dioxane (1.8 mL) and water (0.2 mL) wereadded, and the mixture was degassed with argon for 30 seconds. The vialwas sealed, and the mixture was heated at 100° C. for 60 minutes in amicrowave. The crude mixture was purified directly by silicachromatography (eluent EtOAc/hexanes). The product was subsequentlydissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) wasadded, and the mixture was stirred at rt. LCMS indicated reactioncompletion (removal of Boc groups), and the volatiles were evaporatedunder reduced pressure. To the mixture was added acetonitrile (0.5 mL),water (0.2 mL), and the mixture was filtered through an acrodisc beforepurification by RP-HPLC (0.1% TFA-ACN in 0.1% TFA Water, Column: Gemini5 uM, NX-C18 110 Angstrom, 250×21.2 mm) to give the title compoundExample 21. ES/MS: 497.3 (M+H⁺). ¹H NMR (400 MHz, MeOD) δ 8.61 (s, 1H),8.48 (s, 1H), 7.45-7.41 (m, 2H), 7.14-7.09 (m, 2H), 3.51-3.40 (m, 8H),3.22-3.13 (m, 1H), 3.05 (t, J=7.5 Hz, 2H), 2.50 (s, 3H), 2.34 (q, J=7.5Hz, 2H), 1.35 (d, J=7.1 Hz, 7H).

The following Examples were made in an analogous fashion according toProcedure 7 and are shown below in Table 5. To prepare the belowExamples, different reagents/starting materials were used than some ofthose described in Procedure 7 and are noted in the last column of Table5—“Changes to Procedure 7: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of Procedure 7 were replaced with thedifferent reagents/starting materials noted below.

TABLE 5 Changes to Procedure 7: Different Ex- ES/ Reagents/ am- MSStarting ple Structure m/z ¹H-NMR Materials 22

498.3 ¹H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 8.54 (s, 1H), 8.26 (d, J =2.4 Hz, 1H), 7.83 (dd, J = 8.9, 2.4 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H),3.90 (t, J = 5.3 Hz, 4H), 3.43-3.37 (m, 4H), 3.17 (p, J = 7.1 Hz, 1H),3.05 (t, J = 7.5 Hz, 2H), 2.50 (s, 3H), 2.34 (q, J = 7.6 Hz, 2H), 1.34(d, J = 7.1 Hz, 6H). tert-butyl 4-[5-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan- 2-yl)-2- pyridyl] piperazine-1- carboxylate 23

469.4 ¹H NMR (400 MHz, MeOD) δ 8.70-8.63 (m, 2H), 8.56 (s, 1H), 7.91 (d,J = 2.1 Hz, 1H), 4.55 (s, 2H), 3.71 (t, J = 6.5 Hz, 2H), 3.33 (dt, J =3.3, 2.0 Hz, 4H), 3.20 (p, J = 7.2 Hz, 1H), 3.05 (t, J = 7.5 Hz, 2H),2.58 (s, 3H), 2.35 (p, J = 7.6 Hz, 2H), 1.36 (d, J = 7.1 Hz, 6H).tert-butyl 3-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-7,8-dihydro-5H- 1,6- naphthyridine- 6- carboxylate 24

487.2 ¹H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.51 (s, 1H), 7.89 (s, 1H),3.58 (dt, J = 13.2, 4.5 Hz, 2H), 3.33-3.26 (m, 5H), 3.17 (p, J = 7.1 Hz,1H), 3.05 (t, J = 7.5 Hz, 2H), 2.69 (s, 3H), 2.57-2.27 (m, 6H), 1.35 (d,J = 7.2 Hz, 6H). tert-butyl 4-[4-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan- 2- yl)triazol-1- yl] piperidine-1- carboxylate

Examples 25-40

The following Examples shown below in Table 6 were made in an analogousfashion according to the Procedure indicated in the column of Table 6labeled “Procedure.” To prepare the below Examples, differentreagents/starting materials were used than some of those described inthe indicated Procedure and are noted in the last column of Table6—“Changes to Procedure: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of the indicated Procedure were replacedwith the different reagents/starting materials noted.

TABLE 6 Changes to Procedure: Different Ex- ES/ Pro- Reagents/ am- MSce- Starting ple Structure m/z ¹H-NMR dure Materials 25

573.3 ¹H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.49 (s, 1H), 4.66 (d, J =13.1 Hz, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.86 (dd, J = 6.0, 4.0 Hz, 2H),3.35 (s, 3H), 3.31-2.98 (m, 8H), 2.88-2.76 (m, 1H), 2.61-2.23 (m, 10H),2.01 (q, J = 13.4 Hz, 2H), 1.57 (qd, J = 12.4, 6.4 Hz, 2H), 1.32 (d, J =7.1 Hz, 6H). 6 cis-8-tert- butoxy- carbonyl-5- oxa-8- azaspiro [3.5]nonane- 2- carboxylic- acid 26

462.2 ¹H NMR (400 MHz, MeOD) δ 8.59 (s, 1H), 8.52 (s, 1H), 3.92-3.85 (m,2H), 3.71-3.57 (m, 1H), 3.43 (s, 2H), 3.30 (s, 2H), 3.25-3.18 (m, 2H),3.16- 2.99 (m, 3H), 2.79 (ddt, J = 11.0, 6.3, 2.4 Hz, 2H), 2.41 (s, 3H),2.38-2.19 (m, 4H), 1.31 (d, J = 7.1 Hz, 6H). 1 I-24 27

543.3 ¹H NMR (400 MHz, MeOD) δ 8.57 (d, J = 1.3 Hz, 1H), 8.49 (s, 1H),4.58-4.11 (m, 4H), 3.69-3.53 (m, 1H), 3.40 (t, J = 6.9 Hz, 2H), 3.30 (s,1H), 3.12 (p, J = 7.4 Hz, 1H), 3.02 (t, J = 7.5 Hz, 2H), 2.69-2.49 (m,3H), 2.45 (s, 3H), 2.32 (p, J = 7.6 Hz, 2H), 2.16 (d, J = 14.9 Hz, 1H),2.10-1.89 (m, 5H), 1.84- 1.63 (m, 2H), 1.47 (d, J = 8.8 5 I-36: 2,6-diazaspiro [3.4]octan- 5-one Hz, 1H), 1.31 (d, J = 7.1 Hz, 6H). 28

504.3 ¹H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.49 (s, 1H), 4.42-3.82 (m,5H), 3.51 (s, 1H), 3.30 (s, 2H), 3.12 (p, J = 7.0 Hz, 1H), 3.02 (t, J =7.5 Hz, 2H), 2.44 (s, 3H), 2.32 (p, J = 7.5 Hz, 2H), 2.21-1.70 (m, 8H),1.66-1.50 (m, 3H), 1.31 (d, J = 7.1 Hz, 6H). 5 I-36; 3- methyl-azetidin-3- ol; hydro- chloride 29

516.4 ¹H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.46 (s, 1H), 4.93 (d, J =6.7 Hz, 2H), 4.76 (d, J = 7.8 Hz, 2H), 4.50-4.34 (m, 4H), 3.49 (d, J =10.5 Hz, 1H), 3.27-2.94 (m, 5H), 2.44 (d, J = 1.5 Hz, 3H), 2.31 (p, J =7.4 Hz, 3H), 2.16 (d, J = 11.6 Hz, 2H), 2.05-1.91 (m, 4H), 1.59 (p, J =12.3 Hz, 2H), 1.31 (d, J = 7.0 Hz, 6H). 5 I-36; 2-oxa-6- azaspiro [3.3]heptane 30

557.4 ¹H NMR (400 MHz, MeOD) δ 8.56 (s, 1H), 8.45 (s, 1H), 4.38-4.15 (m,4H), 3.65 (s, 1H), 3.50-3.39 (m, 3H), 3.24 (d, J = 10.0 Hz, 1H),3.16-3.06 (m, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.92 (d, J = 4.8 Hz, 3H),2.57 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.32 (p, J = 7.5 Hz, 2H), 2.08-1.92 (m, 5H), 1.82-1.61 (m, 3H), 1.31 (d, J = 7.1 Hz, 6H). 5 I-36;6-methyl- 2,6- diazaspiro [3.4]octan- 5-one 31

533.3 ¹H NMR (400 MHz, Methanold-d4) δ 8.55 (s, 1H), 8.44 (s, 1H),4.71-4.49 (m, 2H), 3.89 (d, J = 13.8 Hz, 1H), 3.44 (ddt, J = 48.7, 3.5,1.7 Hz, 4H), 3.14-3.08 (m, 2H), 3.04-2.65 (m, 4H), 2.48 (s, 3H), 2.32(q, J = 7.5 Hz, 2H), 2.06 (s, 5H), 1.77-1.56 (m, 2H), 1.32 (d, J = 7.1Hz, 6H). 6 (2R,4R)- 1-tert- butoxy- carbonyl- 4-hydroxy- pyrrolidine- 2-carboxylic acid 32

533.3 ¹H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1H), 8.45 (s, 1H), 4.64(d, J = 13.0 Hz, 2H), 3.98 (d, J = 13.8 Hz, 1H), 3.46-3.37 (m, 4H),3.16- 3.08 (m, 2H), 3.04-2.85 (m, 3H), 2.57 (dt, J = 14.1, 7.3 Hz, 1H),2.48 (s, 3H), 2.31 (p, J = 7.5 Hz, 2H), 2.08 (dd, J = 23.0, 10.5 Hz,5H), 1.81-1.50 (m, 2H), 1.32 (d, J = 7.1 Hz, 6H). 6 (2R,4S)- 1-tert-butoxy- carbonyl- 4-hydroxy- pyrrolidine- 2- carboxylic acid 33

519.3 ¹H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.45 (s, 1H), 6.92(d, J = 9.7 Hz, 1H), 4.76-4.51 (m, 2H), 4.28 (d, J = 12.5 Hz, 1H), 4.06(t, J = 15.6 Hz, 2H), 3.85-3.73 (m, 1H), 3.65 (dt, J = 27.8, 11.9 Hz,1H), 3.38 (s, 5H), 3.20 (d, J = 11.3 Hz, 1H), 3.06 (t, J = 7.5 Hz, 2H),2.96-2.85 (m, 2H), 2.39-2.11 (m, 4H), 1.89-1.59 1, 6 I-31 (m, 2H), 1.35(d, J = 6.9 Hz, 6H). 34

463.5 ¹H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.48 (s, 1H), 6.97(s, 1H), 4.00 (s, 2H), 3.75 (d, J = 12.2 Hz, 2H), 3.59-3.39 (m, 2H),3.31- 3.16 (m, 3H), 3.06 (t, J = 7.5 Hz, 2H), 2.92 (p, J = 6.9 Hz, 1H),2.43-2.24 (m, 4H), 2.24- 2.05 (m, 2H), 1.35 (d, J = 6.9 Hz, 6H). 1, 3I-31 35

422.2 ¹H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.35 (s, 1H),5.01-4.91 (m, 2H), 3.56-3.48 (m, 2H), 3.45-3.39 (m, 2H), 3.27-3.15 (m,4H), 2.49 (s, 3H), 2.20 (d, J = 14.2 Hz, 2H), 1.97-1.80 (m, 2H), 1.35(d, J = 7.1 Hz, 6H). 1 I-26 36

479.2 ¹H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.35 (s, 1H), 4.94(d, J = 9.2 Hz, 1H), 3.99 (s, 2H), 3.74 (d, J = 12.0 Hz, 2H), 3.42 (s,2H), 3.29-3.13 (m, 3H), 2.49 (s, 3H), 2.23 (d, J = 14.3 Hz, 2H),2.16-1.73 (m, 2H), 1.35 (d, J = 7.1 Hz, 6H). 3 Example 35 37

535.3 ¹H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.34 (s, 1H), 4.94(d, J = 9.2 Hz, 2H), 4.69 (dd, J = 25.5, 11.5 Hz, 2H), 4.28 (d, J = 13.1Hz, 1H), 4.06 (t, J = 14.5 Hz, 2H), 3.86-3.75 (m, 1H), 3.75- 3.54 (m,2H), 3.46-3.36 (m, 4H), 3.23-3.12 (m, 2H), 2.90 (t, J = 12.9 Hz, 1H),2.48 (s, 3H), 2.08 (t, J = 16.9 Hz, 2H), 6 Example 35 1.80-1.48 (m, 2H),1.35 (d, J = 7.1 Hz, 6H). 38

491.2 ¹H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.35 (s, 1H), 4.94(d, J = 9.2 Hz, 1H), 3.99 (s, 2H), 3.74 (d, J = 12.0 Hz, 2H), 3.42 (s,2H), 3.29-3.13 (m, 3H), 2.49 (s, 3H), 2.23 (d, J = 14.3 Hz, 2H), 2.16-1.73 (m, 2H), 1.35 (d, J = 7.1 Hz, 6H). 1, 3 I-26, I-20 39

585.2 ¹H NMR (400 MHz, Methanol-d4) δ 10.72 (d, 1H), 8.56 (s, 1H), 8.47(d, 1H), 4.67 (d, 1H), 3.95 (d, 1H), 3.70 (dd, 1H), 3.64-3.52 (m, 1H),3.52-3.44 (m, 1H), 3.46-3.37 (m, 1H), 3.17-3.07 (m, 1H), 3.01 (t, 2H),2.97-2.84 (m, 1H), 2.48 (s, 3H), 2.31 (p, 2H), 2.08 (p, 4H), 1.67 (ddt,2H), 1.32 (d, 6H). 6 (2S,4S)- 1-tert- butoxy- carbonyl- 4- (trifluoro-methyl) pyrrolidine- 2- carboxylic acid 40

538.2 ¹H NMR (400 MHz, MeOD) δ 8.57 (d, J = 1.0 Hz, 1H), 8.47 (s, 1H),4.34 (s, 1H), 3.92-3.48 (m, 8H), 3.27 (d, J = 21.3 Hz, 5H), 3.18-3.05(m, 5H), 3.01 (t, J = 7.5 Hz, 2H), 2.84 (s, 2H), 2.49 (s, 4H), 2.32 (p,J = 7.5 Hz, 3H), 2.20 (d, J = 12.8 Hz, 1H), 2.04 (d, J = 16.2 Hz, 2H),1.32 (dd, J = 7.1, 1.1 Hz, 6H). 3 Example 3; 1-bromo-2- methyl-sulfonyl- ethane

Procedure 8, Example 41

5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-N-methyl-N-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrole-2-carboxamide(Example 41): To a solution of5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-6H-thieno[2,3-b]pyrrole-2-carboxylicacid (I-28) (12.0 mg, 0.033 mmol) in ACN (0.5 mL) was added tert-butyl4-(methylamino)piperidine-1-carboxylate (11 mg, 0.05 mmol), HATU (15 mg,0.04 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.099 mmol) and thereaction mixture was stirred at r.t. overnight. Trifluoroacetic acid(0.25 mL, 3.27 mmol) was added and the reaction mixture was stirred at35° C. for 2 hours. Acetonitrile (0.7 mL) and water (0.15 mL) wereadded, and the crude mixture was filtered through an acrodisc beforepurification by RP-HPLC (0.1% TFA-ACN in 0.1% TFA-Water, Column: Gemini5 uM, NX-C18 110 Angstrom, 250×21.2 mm) to give the title compoundExample 41. ES/MS: 463.2 (M+H⁺)

¹H NMR (400 MHz, Methanol-d4) δ 8.61 (s, 1H), 8.45 (s, 1H), 7.64 (s,1H), 4.61 (dt, J=11.2, 5.9 Hz, 1H), 3.56 (d, J=12.8 Hz, 2H), 3.39-3.36(m, 3H), 3.24-3.13 (m, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.96 (p, J=6.9 Hz,1H), 2.34 (p, J=7.6 Hz, 2H), 2.21-2.07 (m, 6H), 1.39 (d, J=6.9 Hz, 6H).

The following Example was made in an analogous fashion according toProcedure 8 and is shown below in Table 7. To prepare the below Example,a different reagents/starting material was used than some of thosedescribed in Procedure 8 and is noted in the last column of Table7—“Changes to Procedure 8: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of Procedure 8 were replaced with thedifferent reagents/starting materials noted below.

TABLE 7 ES/ Changes to Procedure 8: MS Different Reagents/ ExampleStructure m/z ¹H-NMR Starting Materials 42

435.0 1H NMR (400 MHz, Methanol-d4) δ 8.61 (s, 1H), 8.45 (s, 1H), 7.64(s, 1H), 4.11 (t, J = 5.4 Hz, 4H), 3.40-3.37 (m, 6H), 3.10-2.89 (m, 3H),2.33 (p, J = 7.6 Hz, 2H), 1.39 (d, J = 6.9 Hz, 6H). tert-butylpiperazine-1- carboxylate

Procedure 9: Example 43

tert-butyl(1S,4R,5R)-5-(4-isopropyl-3-methyl-5-(2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate:A solution of tert-butyl(1S,4R,5R)-5-(4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(I-34) (70 mg, 0.187 mmol) in ACN (3 mL) was cooled to 0° C., andN-bromosuccinimide (28.3 mg, 0.16 mmol) (dissolved in 1 mL ACN) wasadded dropwise. After completion of addition, LCMS indicated reactioncompletion. The mixture was quickly concentrated under reduced pressure.The crude residue was dissolved in DME (1 mL) and this solution wasadded to a MW vial containing2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(I-15) (96 mg, 0.318 mmol), XPhos Pd G3 (23.7 mg, 0.028 mmol) and cesiumcarbonate (183 mg, 0.561 mmol). Water (0.2 mL) was added, and themixture was degassed with argon for 30 seconds. The vial was sealed, andthe mixture was heated at 120° C. for 15 minutes in a microwave. Thecrude mixture was purified directly by silica chromatography (eluentEtOAc/hexanes). ES/MS: 548.3 (M+H⁺)

6-(2-((1S,4R,5R)-2-azabicyclo[2.2.1]heptan-5-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-5-yl)-2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine:To a vial with tert-butyl(1S,4R,5R)-5-(4-isopropyl-3-methyl-5-(2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(47 mg, 0.085 mmol) was added methanol (1 mL) and HCl (4M in dioxane,0.5 mL). The reaction was stirred at 35° C. for 30 minutes. The crudemixture was concentrated under reduced pressure, and taken forward tothe next step. ES/MS: 448.2 (M+H⁺)

2-((1S,4R,5R)-5-(4-isopropyl-3-methyl-5-(2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)acetamide(Example 43): To a solution of6-(2-((1S,4R,5R)-2-azabicyclo[2.2.1]heptan-5-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-5-yl)-2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(HCl salt) (40 mg, 0.083 mmol) in 1,2-dichloroethane (1 mL) was added2-bromoacetamide (13.7 mg, 0.1 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.049 mL, 0.33 mmol). The mixturewas stirred overnight at rt. To the mixture was added 0.2 mL TFA, andthe DCE was subsequently removed under reduced pressure. Acetonitrile(0.5 mL), and water (0.2 mL) were added, and the mixture was filteredthrough an acrodisc before purification by RP-HPLC (0.1% TFA-ACN in 0.1%TFA Water, Column: Gemini 5 uM, NX-C18 110 Angstrom, 250×21.2 mm) togive the title compound Example 43. ES/MS: 505.2 (M+H⁺). ¹H NMR (400MHz, Methanol-d4) δ 8.57 (s, 1H), 5.43 (t, J=3.3 Hz, 2H), 5.14 (t, J=3.3Hz, 2H), 4.36-3.95 (m, 3H), 3.87-3.68 (m, 1H), 3.68-3.45 (m, 2H),3.22-3.04 (m, 2H), 2.83-2.62 (m, 1H), 2.60 (s, 3H), 2.52-2.45 (m, 3H),2.40-1.93 (m, 4H), 1.33 (d, J=7.1 Hz, 6H).

The following Examples were made in an analogous fashion according toProcedure 9 and are shown below in Table 8. To prepare the belowExamples, different reagents/starting materials were used than some ofthose described in Procedure 9 and are noted in the last column of Table8—“Changes to Procedure 9: Different Reagents/Starting Materials”. Aperson of ordinary skill in the art will readily recognize whichreagents/starting materials of Procedure 9 were replaced with thedifferent reagents/starting materials noted below.

TABLE 8 Changes to Procedure 9: Different Ex- ES/ Reagents/ am- MSStarting ple Structure m/z ¹H-NMR Materials 44

493.2 1H NMR (400 MHz, Methanol-d4) δ 10.83 (s, 1H), 8.57 (s, 1H), 5.43(t, 2H), 5.15 (t, 2H), 3.99 (s, 2H), 3.74 (d, 2H), 3.53-3.37 (m, 1H),3.31-3.22 (m, 1H), 3.14 (p, 1H), 2.60 (s, 3H), 2.48 (s, 3H), 2.26-2.16(m, 2H), 2.08 (q, 2H), 1.33 (d, 6H). I-33 45

479.2 1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.50 (s, 1H), 5.47 (s, 2H),5.17 (t, J = 3.4 Hz, 2H), 3.97 (s, 2H), 3.71 (s, 2H), 2.48 (s, 3H),2.28-1.99 (m, 6H), 1.34 (d, J = 7.1 Hz, 5H). I-33; I-17 46

519.2 1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 5.43 (s, 2H), 5.15(d, J = 3.5 Hz, 2H), 4.14 (s, 2H), 3.89 (s, 2H), 3.82-3.66 (m, 1H),3.22-3.10 (m, 1H), 2.60 (s, 3H), 2.49 (s, 3H), 2.44- 2.23 (m, 6H),2.23-2.13 (m, 2H), 1.33 (d, J = 7.1 Hz, 6H). I-35 47

503.3 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 4.36-3.88 (m, 3H),3.76 (dd, J = 25.0, 11.6 Hz, 1H), 3.53 (dd, J = 15.9, 9.0 Hz, 1H), 3.27(d, J = 7.6 Hz, 2H), 3.24-3.06 (m, 2H), 3.00 (t, J = 7.5 Hz, 2H),2.86-2.64 (m, 1H), 2.60 (s, 3H), 2.54-2.41 (m, 3H), 2.41-1.90 (m, 6H),1.31 (d, J = 7.0 Hz, 6H). I-34; I-19 48

491.2 1H NMR (400 MHz, Methanol-d4) δ 8.70 (s, 1H), 8.50 (s, 1H), 5.47(t, J = 3.3 Hz, 2H), 5.16 (t, J = 3.5 Hz, 2H), 4.37-3.96 (m, 3H),3.92-3.67 (m, 1H), 3.67-3.48 (m, 1H), 3.25-3.05 (m, 2H), 2.86-2.56 (m,2H), 2.49 (d, J = 4.4 Hz, 3H), 2.42-1.92 (m, 3H), 1.34 (d, J = 7.1 Hz,6H). I-34; I-17 49

505.2 1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.50 (s, 1H), 5.47 (t, J =3.4 Hz, 2H), 5.17 (t, J = 3.4 Hz, 2H), 4.14 (s, 2H), 3.90 (s, 2H), 3.73(tt, J = 11.6, 5.5 Hz, 1H), 3.15 (hept, J = 7.1 Hz, 1H), 2.50 (s, 3H),2.40-2.06 (m, 8H), 1.34 (d, J = 7.1 Hz, 6H). I-35; I-17 50

491.2 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 4.00 (s, 2H), 3.74 (d, J =12.2 Hz, 2H), 3.55-3.36 (m, 2H), 3.32- 3.21 (m, 3H), 3.17-3.00 (m, 3H),2.65 (s, 3H), 2.48 (s, 3H), 2.34 (p, J = 7.6 Hz, 2H), 2.22 (d, J = 14.3Hz, 2H), 2.08 (td, J = 13.9, 9.5 Hz, 2H), 1.32 (d, J = 7.0 Hz, 6H). I-19

Procedure 10: Example 51

tert-butyl4-(4-isopropyl-3-methyl-5-(2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrol-2-yl)piperidine-1-carboxylate:A solution of tert-butyl4-(4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)piperidine-1-carboxylate(I-33) (147 mg, 0.404 mmol) in ACN (4 mL) was cooled to 0° C., andN-bromosuccinimide (64.7 mg, 0.364 mmol) (dissolved in 2 mL ACN) wasadded dropwise. After completion of addition, LCMS indicated reactioncompletion. The mixture was quickly concentrated under reduced pressure.The crude residue was dissolved in DME (2 mL) and this solution wasadded to a MW vial containing2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(I-15) (207 mg, 0.687 mmol), XPhos Pd G3 (51.3 mg, 0.0606 mmol) andcesium carbonate (395 mg, 1.21 mmol). Water (0.2 mL) was added, and themixture was degassed with argon for 30 seconds. The vial was sealed, andthe mixture was heated at 120° C. for 15 minutes in a microwave. Thecrude mixture was purified directly by silica chromatography (eluentEtOAc/hexanes). ES/MS: 536.6 (M+H⁺)

6-(4-isopropyl-3-methyl-2-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrol-5-yl)-2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine:To a vial with tert-butyl4-(4-isopropyl-3-methyl-5-(2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrol-2-yl)piperidine-1-carboxylate(75 mg, 0.14 mmol) was added methanol (1 mL) and HCl (4M in dioxane, 0.5mL). The reaction was stirred at 35° C. for 30 minutes. The crudemixture was concentrated under reduced pressure, and taken forward tothe next step. ES/MS: 436.2 (M+H⁺)

(R)-(4-(4-isopropyl-3-methyl-5-(2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-6H-thieno[2,3-b]pyrrol-2-yl)piperidin-1-yl)(morpholin-3-yl)methanone(Example 51): To a vial with6-(4-isopropyl-3-methyl-2-(piperidin-4-yl)-6H-thieno[2,3-b]pyrrol-5-yl)-2-methyl-7,9-dihydrofuro[3,4-c][1,2,4]triazolo[1,5-a]pyridine(HCl salt) (29 mg, 0.057 mmol) in dichloromethane (1 mL) was added(R)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (20 mg, 0.086mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (33 mg, 0.086 mmol),N,N-diisopropylethylamine (0.03 mL, 0.17 mmol). The mixture was stirred5 hr at rt. To the mixture was added TFA (0.5 mL), and the mixture wasstirred 2 hr at rt. The crude mixture was concentrated under reducedpressure, and acetonitrile (1.5 mL) and water (0.5 mL) were added. Themixture was filtered through an acrodisc before purification by RP-HPLC(0.1% TFA-ACN in 0.1% TFA Water, Column: Gemini 5 uM, NX-C18 110Angstrom, 250×21.2 mm) to give the title compound Example 51. ES/MS:549.1 (M+H⁺). 1H NMR (400 MHz, Methanol-d4) δ 10.76 (s, 1H), 8.56 (s,1H), 5.42 (t, 2H), 5.15 (t, 2H), 4.76-4.57 (m, 2H), 4.28 (dd, 1H), 4.06(t, 2H), 3.84-3.74 (m, 1H), 3.65 (dt, 1H), 3.45-3.37 (m, 4H), 3.14 (p,1H), 2.90 (t, 1H), 2.60 (s, 3H), 2.47 (s, 3H), 2.19-1.98 (m, 2H),1.77-1.55 (m, 2H), 1.33 (d, 6H).

The following Examples were made in an analogous fashion according toProcedure 10 and are shown below in Table 9. To prepare the belowExamples, different reagents/starting materials were used than some ofthose described in Procedure 10 and are noted in the last column ofTable 9—“Changes to Procedure 10: Different Reagents/StartingMaterials”. A person of ordinary skill in the art will readily recognizewhich reagents/starting materials of Procedure 10 were replaced with thedifferent reagents/starting materials noted below.

TABLE 9 Changes to Procedure 10: Different Ex- ES/ Reagents/ am- MSStarting ple Structure m/z ¹H-NMR Materials 52

535.2 1H NMR (400 MeOD) δ 8.69 (s, 1H), 8.50 (s, 1H), 5.47 (t, J = 3.4Hz, 2H), 5.17 (t, J = 3.4 Hz, 2H), 4.76-4.61 (m, 3H), 4.26 (s, 1H), 4.06(t, J = 14.3 Hz, 2H), 3.79 (t, J = 13.8 Hz, 1H), 3.65 (dt, J = 34.9,11.8 Hz, 2H), 3.20- 3.08 (m, 2H), 2.90 (t, J = 12.9 Hz, 1H), 2.48 (s,3H), 2.18-1.99 (m, 3H), 1.76- 1.52 (m, 3H), 1.34 (d, J = 7.1 Hz, 6H).I-17 53

547.3 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 4.76-4.62 (m, 2H), 4.27(ddd, J = 11.0, 6.8, 3.4 Hz, 1H), 4.11-4.00 (m, 2H), 3.87-3.56 (m, 3H),3.45-3.24 (m, 5H), 3.22-2.98 (m, 3H), 2.95-2.84 (m, 1H), 2.64 (s, 3H),2.48 (s, 3H), 2.33 (p, J = 7.6 Hz, 2H), 2.20-1.97 (m, 2H), 1.78-1.51 (m,2H), 1.32 (d, J = 7.4 Hz, 6H). I-19

Procedure 11: Example 54: and Example 55

2-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-5-oxa-8-azaspiro[3.5]nonane(Example 54 and Example 55):2-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-5-oxa-8-azaspiro[3.5]nonane(Example 26) as a mixture of 2 stereoisomers was separated by chiral SFC(Cell 2 4.6×100 mm 5 mic; 45% EtOH)) to give two diastereomers, whichwere arbitrarily assigned as Isomer 1 and Isomer 2.

Isomer 1:2-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-5-oxa-8-azaspiro[3.5]nonane(Example 54) ES/MS: 462.2 (M+H⁺). ¹H NMR (400 MHz, MeOD) δ 8.57 (s, 1H),8.48 (s, 1H), 4.08 (p, J=8.6 Hz, 1H), 3.97 (t, J=5.0 Hz, 2H), 3.33-3.17(m, 6H), 3.16-2.98 (m, 3H), 2.81-2.71 (m, 2H), 2.39 (s, 3H), 2.30 (ddd,J=13.6, 11.0, 7.7 Hz, 4H), 1.31 (d, J=7.1 Hz, 6H).

Isomer 2:2-(5-(8,9-dihydro-7H-cyclopenta[c][1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-isopropyl-3-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-5-oxa-8-azaspiro[3.5]nonane(Example 55) ES/MS: 462.2 (M+H⁺). ¹H NMR (400 MHz, MeOD) δ 8.59 (s, 1H),8.52 (s, 1H), 3.92-3.85 (m, 2H), 3.71-3.57 (m, 1H), 3.43 (s, 2H), 3.30(s, 2H), 3.25-3.18 (m, 2H), 3.16-2.99 (m, 3H), 2.79 (ddt, J=11.0, 6.3,2.4 Hz, 2H), 2.41 (s, 3H), 2.38-2.19 (m, 4H), 1.31 (d, J=7.1 Hz, 6H).

Biological Examples Example A

TLR7/9 Human Peripheral Blood Mononuclear Cell (PBMC) Cell-Based Assay

Human peripheral blood mononuclear cells (PBMCs) consist of lymphocytes,monocytes and dendritic cells that express TLR7, TLR8 and TLR9. Thesecells respond to TLR7, TLR8 and TLR9 ligand stimulation and producecytokines and chemokines in vitro and in vivo. Human PBMCs are thereforesuitable to be used in a cell-based assay to assess the in vitro potencyof a TLR 7, 8, and/or 9 antagonist. The result is expected to be moretranslatable to the pharmacodynamics response in vivo than cellline-based assays.

Cryopreserved human PBMCs from healthy donors were thawed andresuspended in RPMI-1640 media with L-glutamine (Corning) supplementedwith 10% Fetal Bovine Serum (Hyclone) and 1×Penicillin-Streptomycin(Corning). After counting, the cell density was adjusted to 2 millioncells/ml and incubated for 1 hour at 37° C., 5% CO₂ for recovery.Following the recovery, the cells were plated by adding 50 μl per well(100,000 cells) to 384-well cell culture plates (Greiner) containing 250nl of test antagonists in 100% DMSO per well, in a 10 points doseresponse in quadruplicates. PBMCs were incubated in the presence of testantagonists for one hour at 37° C., 5% CO₂ before being stimulated witha TLR7 or TLR9 agonist. GS-986 (Gilead Sciences) was used as the TLR7agonist at a final concentration of 400 nM. ODN-2216 (InvivoGen) wasused as the TLR9 agonist at a final concentration of 3 μM. PBMCs wereincubated in the presence of the test antagonist and the TLR7 (or TLR9)agonist for an additional 6 hours at 37° C., 5% CO₂. At the end of theincubation, the cell culture plates were centrifuged at 500 g for 5 min,and the cell culture supernatant was collected. The level of cytokines(IL-6 and IFNα) in the supernatant was measured byelectrochemiluminescence immunoassays (Mesoscale Discovery) followingmanufacturer's recommended protocols. The level of cytokine measured wasplotted against the test antagonist concentration and fitted to asigmoidal function to determine the EC₅₀, which are shown below in Table6.

TLR8 Human Peripheral Blood Mononuclear Cell (PBMC) Cell-Based Assay

Cryopreserved human PBMCs from healthy donors were thawed andresuspended in RPMI-1640 media with L-glutamine (Corning) supplementedwith 10% Fetal Bovine Serum (Hyclone) and 1× Penicillin-Streptomycin(Corning). After counting, the cell density was adjusted to 2 millioncells/ml and incubated for 1 hour at 37° C., 5% CO₂ for recovery.Following the recovery, the cells were plated by adding 50 μl per well(100,000 cells) to 384-well cell culture plates (Greiner) containing 250nl of test antagonists in 100% DMSO per well, in a 10 points doseresponse in quadruplicates. PBMCs were incubated in the presence ofantagonists for one hour at 37° C., 5% CO₂ before being stimulated withTLR8 agonist. Compound A (Gilead Sciences, U.S. Pat. No. 10,285,990) wasused as the TLR8 agonist at a final concentration of 800 nM. PBMCs wereincubated in the presence of antagonist and the TLR8 agonist for anadditional 6 hours at 37° C., 5% CO₂. At the end of the incubation, thecell culture plates were centrifuged at 500 g for 5 min, and the cellculture supernatant was collected. The level of cytokines (TNFa andIL12p40) in the supernatant was measured by electrochemiluminescenceimmunoassays (Mesoscale Discovery) following manufacturer's recommendedprotocols. The level of cytokine measured was plotted against theantagonist concentration and fitted to a sigmoidal function to determinethe EC₅₀, which are shown below in Table 6. Compound A has thestructure:

TABLE 6 Example TLR-7 EC₅₀ (nM) TLR-8 EC₅₀ (nM) 1 0.11 1.89 2 0.95 3.943 0.77 0.31 4 0.46 0.27 5 0.23 1.76 6 0.35 3.06 7 0.78 3.91 8 0.69 0.149 1.17 0.32 10 0.26 15.32 11 0.32 4.70 12 6.08 4.74 13 1.44 5.84 14 0.584.87 15 0.29 5.26 16 1.46 12.48 17 0.68 15.23 18 0.44 4.42 19 0.14 5.4220 4.63 22.31 21 0.51 1.32 22 0.23 0.66 23 0.33 0.08 24 0.94 0.21 250.05 1.38 26 0.11 0.54 27 0.26 2.55 28 0.15 1.57 29 0.10 1.00 30 0.861.29 31 1.33 6.38 32 1.50 11.27 33 2.33 7.57 34 0.58 1.57 35 0.33 7.8836 4.50 27.61 37 2.95 24.48 38 0.58 0.81 39 3.40 5.01 40 0.27 0.11 410.49 2.56 42 0.78 0.69 43 1.10 2.05 44 4.09 134.97 45 4.00 63.58 46 1.2177.92 47 0.24 0.05 48 0.39 0.36 49 0.41 15.19 50 0.78 34.59 51 2.4696.57 52 1.17 26.67 53 0.62 16.19 54 4.69 5.06 55 0.07 0.18

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure. The descriptionis made with the understanding that it is to be considered anexemplification of the claimed subject matter and is not intended tolimit the appended claims to the specific embodiments illustrated.

1-118. (canceled)
 119. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 120. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 121. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 122. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 123. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 124. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 125. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 126. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 127. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 128. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 129. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 130. The compound ofclaim 119, wherein the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 131. A pharmaceuticalcomposition comprising the compound of claim 119, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier.
 132. The pharmaceutical composition of claim 131, furthercomprising one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.
 133. The pharmaceuticalcomposition of claim 132, wherein the one or more additional therapeuticagents comprises an anti-malarial agent.
 134. The pharmaceuticalcomposition of claim 133, wherein the anti-malarial agent is selectedfrom chloroquine and hydroxychloroquine, or a pharmaceuticallyacceptable salt of each thereof.
 135. A method of inhibiting toll-likereceptor 7 and/or 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 119, or a pharmaceutically acceptable salt thereof.136. A method of inhibiting toll-like receptor 7 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of the compound of claim 119, or apharmaceutically acceptable salt thereof.
 137. A method of inhibitingtoll-like receptor 8 activity in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 119, or a pharmaceutically acceptable salt thereof.138. A method of treating a disease or disorder associated with elevatedtoll-like receptor 7 and/or 8 activity in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of the compound of claim 119, or a pharmaceutically acceptablesalt thereof.
 139. A method of treating a disease or disorder associatedwith elevated toll-like receptor 7 activity in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 119, or a pharmaceuticallyacceptable salt thereof.
 140. A method of treating a disease or disorderassociated with elevated toll-like receptor 8 activity in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 119, or a pharmaceuticallyacceptable salt thereof.
 141. A method of treating an inflammatorycondition in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of the compound of claim 119,or a pharmaceutically acceptable salt thereof.
 142. The method of claim141, wherein the inflammatory condition is selected from inflammatorybowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis,glomerulonephritis, mixed connective tissue disease (MCTD),dermatomyositis, polymyositis, systemic sclerosis, antineutrophilcytoplasmic antibody-associated vasculitis, anti-phospholipid syndrome,autoimmune hemolytic anemia, macrophage activation syndrome driveninflammatory anemia, IgA nephropathy, type I diabetes, non-alcoholicsteatohepatitis, and Sjogren's syndrome.
 143. A method of treatingsystemic lupus erythematosus in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 119, or a pharmaceutically acceptable salt thereof.144. A method of treating cutaneous lupus erythematosus in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 119, or a pharmaceuticallyacceptable salt thereof.
 145. A method of treating lupus nephritis in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of the compound of claim 119, or apharmaceutically acceptable salt thereof.
 146. The method of claim 141,further comprising administering a therapeutically effective amount ofone or more additional therapeutic agents, or a pharmaceuticallyacceptable salt thereof.
 147. The method of claim 146, wherein the oneor more additional therapeutic agents is selected from the groupconsisting of veltuzumab, PF-06835375, eculizumab, milatuzumab, SM-06,SM-03, BT-063, QX-006-N, BOS-161721, AK-101, TNX-1500, theralizumab,daxdilimab, TAK-079, felzartamab, itolizumab, anifrolumab, iscalimab,dapirolizumab pegol, lanalumab, LY-3361237, JNJ-55920839, UBP-1213,DS-7011, PFI-102, BIIB-059, obexelimab, talacotuzumab, vobarilizumab,TE-2324, PRV-3279, chloroquine, hydroxychloroquine, hydroxychloroquinesulfate, COV-08-0064; GNKS-356, AVO-101, rozibafusp alfa, VRN-02,annexuzlimab, ALPN-101, bendamustine hydrochloride, BMS-986256, NKTR-35,atacicept, telitacicept, BMS-986256, M-5049, KZR-616, KPG-818,verdinexor, ALPN-303, valziflocept, LA-1, cenerimod, prednisone,corticotropin, deucravacitinib, CPL-409116, CS-12192, tofacitinibcitrate, ISB-830, DV-1079, julemic acid, iberdomide, TAM-01, BML-258,brepocitinib, SDC-1801, SDC-1802, ICP-330, NTR-441, dalazatide,GSK-2646264, SKI-O-703, lanraplenib (GS-9876), GNS-1653, HMPL-523,RSLV-132, interleukin-2 follow-on biologic, interleukin-2 Anteluke,interking recombinant human interleukin-2, ILT-101, CUG-252, DZ-2002,PEGylated HLA-x (SLE), AC-0058, fenebrutinib, XNW-1011, tirabrutinibhydrochloride, branebrutinib, elsubrutinib, orelabrutinib, DWP-213388,INV-103, R-salbutamol sulphate, anchorins, NIK-SMI1, X-6, INV-17, OshadiD, baricitinib, upadacitinib, filgotinib, itacitinib, INCB-54707,delgocitinib, DWP-212525, CKD-971, as mometasone, betamethasone,forigerimod, anandamide, DCB-SLE1, arsenic trioxide, tairuimide, TV-4710(edratide), allogeneic human umbilical cord-derived mesenchymal stemcell therapy (hUC-MSCs), LC-200, BI-705564, SM-934, GX-101, TXR-712,TXR-711, CIT-013, MHV-370, Panzyga®, TPX-6001, TPX-7001, artenimol, andAMG-592, or a pharmaceutically acceptable salt of any of the foregoing,or any combination thereof.